CN112915208B - Composition with function of perfecting diversity of personalized intestinal flora and application thereof - Google Patents
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Abstract
The invention discloses a composition with a function of perfecting and individualizing diversity of intestinal flora and application thereof. The composition is proved to have bidirectional regulation effect on intestinal flora from four levels of gene, function, system and disease, and has the effects of preventing or treating metabolic, immunologic function, skin, psychonervosis, digestive system, sex hormone deficiency and other diseases by perfecting and maintaining the diversity of personalized intestinal flora.
Description
Technical Field
The invention relates to the technical field of pharmaceutical compositions and the like, in particular to a composition with a sound personalized intestinal flora diversity function and application thereof.
Background
As the medical frontier of the later antibiotic age, one of the most important scientific and technological achievements in the last 10 years is that the mutual benefit, simple benefit or parasitic relation between the intestinal flora and the human body and the important role of the intestinal flora on the maintenance of the physiological function constancy of the host human body are more and more clearly understood. Many diseases that cannot be cured by modern medicine, including metabolic, immunological, and neuro-psychiatric diseases, are closely related to the imbalance of the intestinal flora.
The intestinal flora makes up the deficiency of human material and function through the diversity of the intestinal flora and the symbiotic relationship of the intestinal flora and the host human body. There are about 20,000-25,000 genes in the human body, and there are at least 300 ten thousand genes in the microorganisms symbiotic in and out of the human body. In other words, the human body itself has genes less than 1%, and microbial genes living on the inner and outer surfaces of the human body account for 99% or more. The intestinal flora is the largest population, and the huge gene variety provides multiple functional assistance for the host human body. Its usefulness to human health can be briefly summarized as: provide nutrition, help protect against attack by harmful foreign pathogens, promote the maturation and maintenance of the normal function of the immune system, help maintain a constant state of various physiological functions (including various physiological activities such as mental nerves), and the like. These advances are renewing the traditional medical understanding of metabolic, immune functional, and neuro-psychiatric diseases, such that gut flora science is moving from the research level into the applied treatment phase (Schimidt et al, cell, 2018).
Unfortunately, the intestinal flora ecology symbiotic with the human body is rapidly deteriorating. The development of public health, the wide application of pesticides and chemical medicines, environmental pollution, the change of dietary structure and the popularization of caesarean section lead to the crisis of the inheritance and maintenance of intestinal bacteria by taking the antibiotics invented in the second war as a first step. The diversity of intestinal flora is represented by the existence of various weak strains. However, the disadvantaged bacteria are often in an unfavorable state in competition and have weak tolerance to environmental factors. The weakening or even disappearance of the function of the intestinal flora can lead to a stronger function of a few of the populations of the vigour, and the intestinal flora is trapped in a state of dysbiosis (dysbiosis). Concomitant with this is a rapid increase in the incidence of metabolic, immunological, and neuro-psychiatric diseases, by a factor of two or even several tens. Typical diseases such as metabolic abnormality, type II diabetes, are estimated to reach 1.14 hundred million in Chinese patients in 2017 (status of diabetes epidemics and control in Chinese adults). Also like autism, which is originally a very rare disease, 2019 "chinese autism education recovery development report 3" shows that chinese patients may have exceeded 1000 ten thousand. Metabolic diseases mainly include: type II diabetes, obesity, cardiovascular disease, cerebrovascular disease, hyperlipidemia, hypertension, hyperuricemia, etc.; immune diseases mainly include: food/drug/foreign body allergy, eczema, type I diabetes, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, multiple sclerosis, rheumatoid, asthma, cancer, and the like; and psychoneurological disorders mainly include: autism, depression, bipolar disorder, parkinson's disease, alzheimer's disease, and the like. These diseases involve a variety of systems, seemingly poorly associated, but their common pathological basis may be related to an imbalance in gut flora function. Professor martin university in new york refers to these diseases as modern epidemics in their book "disappearing microorganisms", the cause of which may be derived from an imbalance in the intestinal flora.
The intestinal flora is characterized by individuation, and the sign of healthy microecology is diversity. Individualization refers to the specificity of intestinal bacterial species maintained by an individual, and is related to background factors such as heredity, culture and environment. Generally formed around three years old and basically maintained for life. The similarity between people with the closest relationship of blood relationship (siblings) is often less than 50%, so scientists compare the intestinal flora with fingerprints. This is very important, and the goal of strengthening and maintaining the diversity of intestinal flora and maintaining the microecological balance must be achieved on the premise of individualizing the intestinal flora.
Beneficial and harmful bacteria are concepts that have prevailed in recent decades. However, this concept is too simplistic to properly demonstrate the function of the intestinal flora and may even be misleading. Because most enterobacteria are bifacial, under certain conditions they help the host, but under other conditions they can harm the host. For example, helicobacter is a pathogenic bacterium causing gastric ulcer and gastric cancer, but a large number of research data suggest that the disappearance of helicobacter results in a large increase in the risk of developing various diseases such as obesity, asthma, allergy, and esophageal cancer (Li j. Also, clostridium difficile is usually a harmless indigenous bacterium, but pseudomembranous colitis caused by abnormal increase of clostridium difficile is a fatal disease when intestinal flora microecology is out of balance due to antibiotics and the like. In the united states, 29,000 people died of pseudomembranous colitis in 30 days or less after just 2011 (the united states health and public service department news agency, 2015.2.25). Therefore, the method overcomes the limitations of beneficial bacteria and harmful bacteria, does not make specific strains stronger or weaker, and regulates the balance of the functions of the whole flora, thereby being the key for perfecting and maintaining the diversity of the intestinal flora. The academia has noticed this point and emphasizes the maintenance of a harmonious microecology through the interdependent, mutually inhibitory mechanisms of various intestinal bacteria, which in turn maintains the health of the human body, preventing and treating the related chronic diseases (Cho and blast, nature 2012).
The use of probiotics to improve the imbalance of intestinal flora has a long history. Although not repudiated for its usefulness, probiotics have three limitations from a personalization and diversity perspective. First, probiotics act as a bystander, and multiple clinical trials demonstrate that probiotics do not colonize the intestinal tract (Kristensen et al, genome Med 2016). Secondly, the species provided by probiotics are limited and cannot meet the requirements of diversity. Third, as a passerby, probiotics are the subject of competition for the usual in vivo bacteria. Probiotics can hinder the recovery of individualized resident flora and become a risk factor for disrupting resident flora balance (Suez J, et al., cell, 2018).
Many enterobacteria ferment components that the person cannot digest and absorb as their own source of nutrition, which is called prebiotics. Because prebiotics provide nutrition to the individual's indigenous gut bacteria, they are theoretically superior to probiotics in terms of healthiness and maintenance of a personalized gut flora. However, studies have generally been directed to the increase of certain beneficial bacteria, or the reduction of harmful bacteria. There is currently no study of prebiotics on the overall structural function of the gut flora (Sanders ME et al, nature rev.2019).
The invention consolidates acquired foundation by traditional Chinese medicine, combines traditional Chinese medicines for tonifying spleen and qi, eliminating dampness and activating blood, and multiple types of intestinal flora energy substrates to strengthen and maintain individuation and diversity of intestinal flora so as to solve the problems.
From search investigations, there is no similar patent document or paper document. The relevant patent documents investigated in mainland china and taiwan are as follows: CN201510036300, CN201510344591, CN201510417997, cn201510471077, CN201610189936, CN201810722697, CN _ 105992 \A, CN _105532904_A, CN _105535580_A, CN _105641521_A, CN _105670047, CN _105685868A, CN _105707628_A, CN _105749099_A, CN _105797003a, CN _106036856_A, 106943423A, CN _107364 _A, CN _1074646468716A, CN _107504949A, CN 108159090 108090A, CN 1081081081081081087920A, CN 749620196499622A, CN 74962019660749622 a, CN 74969896989198968725 a, CN 300961059 _A, CN 7496961056A, CN 749610596105961056A, CN 74300961059610574961056A, CN 743009610596105961056A, CN 74300961059610596105961056A, TW 1087496105961056, CN 74961056A, CN 749698961059610596989198969891989A, TW A, CN 74969896989698966A, CN 74961056A, TW W.
Disclosure of Invention
The invention relates to an intervention scheme for strengthening and maintaining personalized intestinal flora diversity by applying the acquired theory of traditional Chinese medicine, a composition with the function of strengthening and personalizing the intestinal flora diversity and a medicine obtained from the composition.
The invention firstly proves the usefulness of the gene analysis technology of the intestinal flora to the individual diversity of the intestinal flora. The improvement of the high-channel intestinal flora gene analysis technology in the last 10 years provides a technical means for molecular-level intestinal flora gene analysis, functional gene abundance enrichment prediction and metabolic pathway analysis. The species structure of the colony can be accurately known through 16S/ITS diversity sequencing. The 16S rRNA gene is a gene encoding the small subunit of the ribosome of prokaryotes and is the most common and useful marker in the taxonomic study of bacterial systems. The gene sequence comprises 9 variable regions and 10 conserved regions, the conserved regions reflect the relativity between species, and the variable regions can reflect the difference between species. The invention carries out OTUs (Operational Taxonomic Units) annotation by amplifying and sequencing v4 variable regions. Picrast is the tool that was developed at the earliest to predict microbial community function based on the 16SrRNA gene sequence, and by analyzing the composition of gene function of the genome of a microorganism that has been sequenced, the composition of functional genes in a sample can be predicted by species composition obtained by 16s sequencing. Based on the prediction of PICRUSt function of 16SrDNA sequence, gene prediction and metabolic pathway prediction of different levels (1-3) are obtained.
Although the technology of gene analysis of intestinal flora has advanced sufficiently, it cannot fully explain the overall appearance of intestinal flora, and even the knowledge of intestinal flora is still one corner of iceberg. By matching with the analysis of the system phenotype level, the limitation of intestinal flora gene analysis on the comprehension of the overall flora work can be compensated. The invention utilizes the Bristol feces scale as a comprehensive index of the diversity and health state of the intestinal flora. It is based on the fact that, first, the nomenclature of probiotics, the professor guanga, japan institute of physico-chemical research, points out that observing stool shape and odor is the best indicator of the health of intestinal flora based on his lifelong research experience and results (report on interview by professor guanga, 2015). Second, one of the largest analyses of the intestinal flora of the population to date has found that the bristol fecal scale is the most comprehensive indicator of the diversity of intestinal flora (Falony et al science 2016).
The invention aims to further prove that the composition has the effect of improving the organism function by improving the intestinal flora, and detects some representative laboratory detection indexes of related diseases. These include an improvement in dyslipidemia (serum total cholesterol, serum triglycerides, serum low density lipoprotein cholesterol, serum high density lipoprotein cholesterol), an improvement in dyslipidemia (fasting plasma glucose, glucose tolerance test), an improvement in hyperuricemia (serum uric acid), an improvement in renal function index (serum creatinine, estimated glomerular rate filtration), and an improvement in hepatic function index (serum glutamic-pyruvic transaminase, serum glutamic-oxalacetic transaminase).
The core of the invention is that the recognition limit of harmful bacteria and beneficial bacteria is broken through without the increase or decrease of individual strains, and the aim of perfecting and maintaining the diversity of the personalized intestinal flora is achieved by focusing on the integral function balance of the intestinal flora. The invention proves the usefulness of the composition for perfecting and maintaining the diversity of the personalized intestinal flora through bidirectional regulation on the intestinal flora and functional genomes from three levels of molecules, functions and systems. These effects can help the human body to achieve the purposes of consolidating the acquired foundation of the traditional Chinese medicine, namely helping the development and growth of the human body, maintaining the constancy of the physiological system after the adult, and preventing, or treating, or assisting in treating the diseases related to the imbalance of the intestinal flora. Through the detection of the data of the representative laboratories of the related diseases, the level 4, namely the disease level, proves that the composition of the invention can play a role in preventing and treating the related diseases, particularly the metabolic dysfunction disease, the immunologic dysfunction disease, the skin disease and the mental and neurological disease by strengthening and maintaining the diversity of the personalized intestinal flora.
The invention is realized by the following technical scheme: a novel intervention scheme is characterized in that the theory of Chinese medicine for consolidating acquired foundation is applied, chinese medicines for tonifying spleen and qi, eliminating dampness and promoting blood circulation are selected, the compound compatibility is personalized, energy substrates required by diversified intestinal tract bacteria break through the limitations of harmful bacteria and beneficial bacteria, and the function balance and diversity of the integrated intestinal tract flora are focused to prevent, or treat or assist in treating diseases caused by the imbalance of the intestinal tract flora. The composition shows definite bidirectional regulation effect on intestinal bacteria and intestinal bacteria prediction function genome, which shows that the composition has good regulation effect on intestinal flora structure and diversity. Meanwhile, the composition also shows good bidirectional regulation effect on the index of the quantity of the Bristol feces, and supports the effectiveness of the composition on the structure and diversity of intestinal flora from the system phenotype level. Through representative laboratory tests on related diseases, the composition has good improvement effects on blood sugar, blood fat, serum uric acid, renal function and liver dysfunction, and further proves the usefulness of perfecting and maintaining the diversity of personalized intestinal flora on the related diseases. In summary, the invention demonstrates the beneficial effects of the intervention regimen and composition on the well-being and maintenance of the diversity of the personalized gut flora at the molecular level, functional level, overall human level, and 4 levels of representative disease.
The invention is realized by the following technical scheme: compositions based on intervention regimens, and uses. The compatibility of the medicines comprises traditional Chinese medicines for tonifying spleen and qi, eliminating dampness and activating blood, and multiple intestinal flora energy substrates (water-soluble and water-insoluble dietary fibers). All Chinese medicines or Chinese medicine extracts can be purchased from medical companies or manufacturers, and the products all meet the national quality standards.
The invention provides a composition with a sound and personalized intestinal flora diversity function, and the composition can effectively improve the intestinal flora function of a human body after being taken.
A composition with personalized intestinal flora diversity function comprises components for invigorating spleen and invigorating qi, components for eliminating dampness and promoting blood circulation, and intestinal bacteria energy substrate.
Preferably, the spleen-invigorating and qi-tonifying component includes, but is not limited to, one or more of ginseng, ginseng extract, american ginseng and American ginseng extract. Ginseng radix, ginseng radix extract, radix Panacis Quinquefolii, and radix Panacis Quinquefolii extract can be used for invigorating primordial qi, invigorating spleen, and benefiting lung. The Ginseng radix comprises crude Ginseng radix, or intermediate product of Ginseng radix after simple pretreatment, or pulverized or ground Ginseng radix powder or granule. The radix Panacis Quinquefolii comprises radix Panacis Quinquefolii crude drug, or simple pretreated radix Panacis Quinquefolii intermediate product, or crushed or ground radix Panacis Quinquefolii powder or radix Panacis Quinquefolii granule, etc. The ginseng extract is an initial extract extracted from ginseng by the existing extraction method or an extract after simple pretreatment, and the like, and the main active ingredients are ginsenoside, ginseng polysaccharide, polypeptide, amino acid, volatile oil, inorganic elements and the like, and the general content is 0.0001-10%. The American ginseng extract is a primary extract extracted from American ginseng by the existing extraction method or an extract obtained by simple pretreatment, and the like, and the main active ingredients are ginsenoside, volatile oil, amino acid, polysaccharide, flavonoid, inorganic elements and the like, and the content is generally 0.0001-10%. The ginseng extract or the American ginseng extract can be obtained by self-extraction according to the existing method, and the existing commercially available products can also be directly adopted.
Preferably, the dampness eliminating and blood circulation promoting ingredients comprise dampness eliminating ingredients and blood circulation promoting ingredients, wherein the dampness eliminating ingredients comprise but are not limited to poria cocos and a mixture of one or more of poria cocos extracts; the blood activating component includes but is not limited to one or more of nattokinase, natto and natto extract. The Poria comprises one or more of Poria crude drug, or processed Poria pieces, poria blocks or Poria slices, and also comprises processed Poria powder or Poria granule, etc. The Poria extract is total extract extracted from Poria by existing extraction method, or separated extract such as pachyman, etc., and can be extracted by oneself or commercially available product. The nattokinase can be directly prepared from the existing commercial product, or natto and natto powder or natto extract can be used for replacing nattokinase. The final dosage of natto, natto powder, and natto extract may be determined by taking the desired amount of active. In the scheme, the nattokinase dissolves thrombus through two ways, namely direct and indirect. It can stimulate vascular endothelial cells to produce tissue-type plasminogen activator (t-PA), which activates plasminogen to plasmin, dissolves fibrin and directly dissolves thrombus; at the same time, the prourokinase in the human body is activated into urokinase, and the urokinase and t-PA together activate plasminogen to indirectly dissolve thrombus.
Preferably, the gut bacteria energy substrate includes, but is not limited to, water-soluble dietary fiber, water-insoluble dietary fiber, or any combination of both.
The water-soluble dietary fiber comprises one or more of konjac flour, glucomannan, crude laminarin, pectin, alginic acid, glucan, guar gum, inulin and dried orange peel, or one or more of food materials or medicinal materials containing the components. For example, tangerine peel can be selected to replace or supplement pectin.
Preferably, the water-insoluble dietary fiber comprises one or more of Cellulose (Cellulose), hemicellulose (hemicellulose) and lignin (Methyl Cellulose). Cellulose is a macromolecular polysaccharide in which glucose contained in plant cell walls is linked in straight lines. Each cellulose molecule aggregates (crystallizes) to form microfibers characterized by the fact that adjacent microfibers are oriented in the same direction to form tightly bound bundles that are insoluble in water. Hemicellulose is a generic term for water-insoluble polysaccharides contained in the cell wall of explants excluding cellulose. It is characterized by that it is a hetero polymer formed from various sugars (xylose, mannose, glucose and arabinose) which are irregularly combined together. Lignocellulose is an organic flocculent fibrous substance obtained by processing natural wood. For example, common water-insoluble dietary fibers include, but are not limited to, ganoderma lucidum, black fungus, tremella, champignon, agaric, hericium erinaceus, gastrodia elata, phellinus igniarius, poria cocos, psyllium husk, and the like. These materials are commercially available or available in drug stores.
Preferably, the beverage further comprises one or more of momordica grosvenori, momordica grosvenori extract, almond extract, perilla seed and perilla seed extract. The fructus momordicae can be used for introducing medicine into spleen and large intestine channels, can also be used as a natural healthy sweetener, and has the function of improving the mouthfeel in the composition. The composition may also comprise semen Armeniacae amarum, semen Armeniacae amarum extract, fructus Perillae, and fructus Perillae extract. The almond dietary fiber content exceeds 10%, and the almond dietary fiber is rich in unsaturated fatty acid and has the effect of moistening the intestines. Perilla seed is rich in unsaturated fatty acids (> 50%) and essential amino acids. It can provide energy substrate for intestinal flora and also has the function of relaxing bowel.
One of the components may have two or more functions, for example, the tuckahoe or tuckahoe extract has the functions of strengthening the spleen and eliminating dampness and belongs to a ministerial medicine of the composition, and simultaneously contains more than 90 percent of water-insoluble dietary fiber and has the functions of an assistant. For example, the psyllium husk contains both water-soluble dietary fiber and water-insoluble dietary fiber, and thus can function as both water-soluble dietary fiber and water-insoluble dietary fiber.
As a preferred scheme, the spleen-invigorating and qi-tonifying component is one or more of ginseng, ginseng extract, american ginseng and American ginseng extract; the dampness eliminating and blood circulation promoting component comprises a dampness eliminating component and a blood circulation promoting component, wherein the dampness eliminating component comprises but is not limited to one or a mixture of poria cocos and poria cocos extracts; the blood activating component comprises but is not limited to one or more of nattokinase, natto and natto extracts, and the daily composition mainly comprises:
the addition amount of the nattokinase is directly obtained by conversion according to the required activity amount; the addition amount of the natto and the natto extract is calculated by the activity unit containing natto kinase;
in the present invention, the daily dose may be taken once or in two or more portions.
As a more preferable scheme, the daily amount mainly consists of:
the addition of the nattokinase is directly obtained by conversion according to the required activity unit; the addition amount of the natto and the natto extract is calculated by the activity amount of the natto kinase contained in the natto and the natto extract;
as a preferable scheme, the feed also comprises 0.1 to 3 grams (more preferably 0.3 to 1.5 grams) of the momordica grosvenori or 0.001 to 0.5 grams (more preferably 0.001 to 0.2 grams) of the momordica grosvenori extract; or simultaneously or independently comprises 0.25-1g of almond and/or 0.25-1g of perilla seed. The scheme has therapeutic or relieving effect on constipation patients.
In the composition, when the dampness eliminating component is poria cocos, the addition amount of poria cocos crude drug is 0.1-5 g; when selecting the tuckahoe extract, 0.001 to 2 grams of the tuckahoe extract is required to be added.
The water-soluble dietary fiber and the water-insoluble dietary fiber are respectively independent, and further preferably: the water-soluble dietary fiber accounts for 20-60% of the total amount of the formula; the water-insoluble dietary fiber accounts for 20-60% of the total amount of the formula. The total adding amount of the water-soluble dietary fiber and the water-insoluble dietary fiber is 1 to 10 grams according to the daily amount.
As a specific preferable scheme, the spleen-invigorating and qi-tonifying component can be 0.1-1.2 g of ginseng or/and American ginseng by daily amount, or 0.005-0.05 g of ginseng extract or/and American ginseng extract, or a combination of the two schemes.
Specifically, the moisture-eliminating component may be 0.2 to 4 g of poria cocos or 0.001 to 2 g of poria cocos extract, and the blood-activating component may be 500 to 4000Fu of nattokinase or 10 to 100 g of fresh natto, and more preferably 10 to 50g, or 5 to 50g of dried natto powder or crude natto extract. The tuckahoe or/and tuckahoe extract can be used as a ministerial drug to play an auxiliary role in invigorating the spleen and tonifying qi, and can also be used as a water-insoluble dietary fiber to play an auxiliary role.
As a specific preferred embodiment, the composition comprises the following composition, calculated on a daily basis:
as a specific preferred embodiment, the composition comprises the following composition, calculated on a daily basis:
the invention also provides application of the composition in any one of the technical schemes in preparation of a medicine with a function of perfecting the diversity of the personalized intestinal flora.
The invention also provides application of the composition in any technical scheme in prevention, treatment or adjuvant treatment of diseases related to the imbalance of intestinal flora.
The invention provides an intervention scheme for strengthening and maintaining diversity of intestinal flora by applying the acquired theory of traditional Chinese medicine, and the scheme utilizes traditional Chinese medicine for strengthening spleen, eliminating dampness and activating blood circulation, and is matched with a compound intestinal flora energy substrate to strengthen and maintain the diversity of personalized intestinal flora by bidirectional regulation of functions of the intestinal flora.
Preferably, the medicament is a medicament for preventing, treating or assisting in treating diseases related to the imbalance of the intestinal flora.
The invention also discloses application of the composition in any one technical scheme in perfecting the diversity of the personalized intestinal flora. For example, it can be used in the form of a medicament for the application of a robust personalized intestinal flora diversity. Furthermore, the invention provides an application of the composition in preventing, treating or assisting in treating diseases related to the imbalance of the intestinal flora.
Preferably, the imbalance in intestinal flora comprises a low diversity in the species and function of intestinal flora.
Preferably, the number of the types of the intestinal flora and the functional genome is relatively large, and the number of the types of the intestinal flora and the functional genome is relatively small.
Preferably, the intestinal flora imbalance related diseases comprise one or more of metabolic diseases, immune diseases, skin system diseases, neuro-psychiatric diseases, digestive system diseases and sex hormone hypofunction related diseases related to intestinal flora imbalance.
Preferably, the metabolic dysfunction disease comprises borderline diabetes, type II diabetes, obesity, cardiovascular disease, cerebrovascular disease, hyperlipidemia, hypertension, hyperuricemia, and renal dysfunction.
The diseases caused by high uric acid mainly comprise but are not limited to gout, acute/chronic arthritis caused by high uric acid, uric acid-derived kidney stones, and acute or chronic renal dysfunction diseases caused by uric acid.
Preferably, the immunological disorder comprises food/drug/foreign body allergy, eczema, type I diabetes, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, multiple sclerosis, rheumatoid, chronic fatigue, asthma, cancer.
Preferably, the dermatological disease comprises atropine dermatitis associated with an imbalance in the intestinal flora, psoriasis, eczema, acne, skin roughness, and skin aging.
Preferably, the neuro-psychiatric disorder comprises depression, bipolar disorder, autism, schizophrenia, fibromyalgia, insomnia, parkinson's disease, and Alzheimer's disease.
Preferably, the digestive system diseases comprise constipation, diarrhea, fatty liver and liver cirrhosis.
Preferably, the sex hormone deficiency-related diseases include primary and secondary sexual hypoevolutism in children and adolescents, related abnormalities and diseases in female physiological cycle and gestation period, osteoporosis due to estrogen deficiency in postmenopausal women, male and female sexual dysfunction, and climacteric syndrome.
Preferably, the drug can enhance the body's biodegradation function for exogenous toxic substances. Exogenous toxic substances, including pesticides, herbicides, food additives, plastic residues, rubber residues, environmental pollutants, heavy metals, and other harmful chemicals.
Specifically, the exogenous toxic substance preferably comprises one or more of halogenated benzoic acid, halogenated cyclohexane, halogenated benzene, caprolactam, 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine, dioxin, aminobenzoate and xylene.
The invention proves that the composition can inhibit the vigorous growth and functional genome thereof, enhance the weak growth and functional genome thereof, promote the body phenotype to converge towards the intermediate type, and has good bidirectional regulation effect on intestinal flora. The composition can be used for treating or preventing diseases related to intestinal flora imbalance, such as metabolic, immunologic, and psychonergic diseases, by strengthening and maintaining individual intestinal flora diversity.
Drawings
FIG. 1 is a Bristol Stool Chart;
FIG. 2a is a graph showing the negative correlation between the increase in relative abundance of each phylum of bacteria and the relative abundance before administration (the left graph is a graph showing the results 14 days after administration, and the right graph is a graph showing the results 30 days after administration);
FIG. 2b is a graph showing the negative correlation between the increase in relative abundance of each class of bacteria and the relative abundance before administration (the left graph shows the result 14 days after administration, and the right graph shows the result 30 days after administration);
FIG. 2c is a graph showing the negative correlation between the increase in relative abundance of each bacterium order and the relative abundance before the administration (the left graph shows the result 14 days after the administration, and the right graph shows the result 30 days after the administration);
FIG. 2d is a graph showing the negative correlation between the increase in relative abundance of each bacterial family and the relative abundance before the administration of the drug (the left graph is a graph showing the results 14 days after the administration of the drug, and the right graph is a graph showing the results 30 days after the administration of the drug);
FIG. 3 is a graph showing the results of inhibition of the relative abundance of firmicutes of the phylum Mycoplasma according to the protocol provided in the example (the left graph shows the results 14 days after administration, and the right graph shows the results 30 days after administration);
FIG. 4 is a graph showing the results of the protocol provided in the example for a significant improvement in the relative abundance of Bacteroides bacteroidetes, phylum II (the left graph shows the results after 14 days of administration, and the right graph shows the results after 30 days of administration);
FIG. 5 is a graph showing the results of the protocol provided in the example significantly improving the relative abundance of proteobacteria of the third predominant phylum (the left graph is a graph showing the results 14 days after administration, and the right graph is a graph showing the results 30 days after administration);
FIG. 6 is a graph of the results of the effect on the relative abundance of the phylum amblyopia after 14 days following administration of the regimen provided in the examples;
FIG. 7 is a graph of the results of the effect on the relative abundance of the phylum amblyopia 30 days after administration of the regimen provided in the examples;
FIG. 8 is a graph showing the results of the effect on the firmicutes/Bacteroides ratio at 14 days after administration of the regimen provided in the examples;
FIGS. 9a to 9c are graphs showing the effect of the regimen provided in the examples on the relative abundance of Mao Luojun, bacteroides dirichi, and Bacteroides after administration for 14 days/30 days, respectively;
FIG. 10 is a graph of the results of a correlation analysis of the change in the total predicted metabolic pathway (two hundred and thirteen total) after administration of the regimen provided in the examples and the relative abundance before administration;
FIG. 11 is the relative abundance changes of the genome associated with cellular transformation after administration of the regimen provided in the examples at 14/30 days;
FIG. 12 is the relative abundance changes of the transcription associated genomes after the regimen provided in the example was taken for 14/30 days;
FIG. 13a is the relative abundance change of the cell membrane transport associated genome after administration of the regimen provided in the examples for 14/30 days;
FIG. 13b is the change in relative abundance of the electron transport vector-associated genome after administration of the regimen provided in the examples at 14/30 days;
FIG. 13c is the relative abundance change of the inorganic ion transport associated genome after administration of the regimen provided in the examples for 14/30 days;
FIG. 13d is the relative abundance change of ion channel associated genomes after administration of the regimen provided in the examples for 14/30 days;
FIG. 14 is the relative abundance changes of the relevant genomes for cell regeneration and repair after 14/30 days following dosing of the protocol provided in the examples;
FIG. 15 is the relative abundance changes of cell growth and death-related genomes after 14/30 days following dosing of the protocol provided in the examples;
FIG. 16 is the relative abundance changes of the apoptosis-associated genome after administration of the regimen provided in the examples for 14 days/30 days;
FIG. 17 is the relative abundance change of ubiquitin system-associated genomes after the regimen provided in the examples was taken for 14/30 days;
FIG. 18 is the change in relative abundance of glycan biosynthesis and metabolism after administration of the regimen provided in the examples for 14/30 days;
FIG. 19 is the relative abundance change of the heterologous degradation associated genomes after administration of the regimen provided in the examples for 14 days/30 days;
FIGS. 20a and 20b are the relative abundance changes of the drug metabolizing cytochrome Cyp450 and the heterologous metabolizing cytochrome Cyp450, respectively, after the regimen provided in the examples was taken for 14 days/30 days;
FIG. 21a is the change in relative abundance of genes involved in terpene and polyketide biosynthesis after 14/30 days following dosing in the protocol provided in the examples;
FIG. 21b is the relative abundance changes of genes involved in type II polyketide biosynthesis after administration of the regimen provided in the examples for 14 days/30 days;
FIG. 22 is a graph showing the relative abundance changes of the genes involved in the biosynthesis of coenzyme and vitamin after administration of the regimen provided in the examples for 30 days;
FIG. 23a is the change in relative abundance of genes involved in vitamin b1 and b2 synthesis after administration of the regimen provided in the examples for 30 days;
FIG. 23b is a graph showing the change in relative abundance of vitamin b6 and folate synthesis-associated genes, after administration of the protocol provided in the example for 30 days;
FIG. 23c is the change in relative abundance of the vitamin b12 synthesis gene after administration of the regimen provided in the examples for 30 days;
FIG. 24 is a graph showing the relative abundance changes of lipoic acid metabolism-related genes after administration of the regimen provided in the examples at 14/30 days;
FIG. 25 is a graph showing the relative abundance changes of the carbohydrate metabolism-related genes after the regimen provided in the examples was administered for 14 days/30 days;
FIG. 26a is the change in relative abundance of genes associated with lipid metabolism after administration of the regimen provided in the examples for 14 days/30 days;
FIG. 26b is the relative abundance change of bile secretion-associated genes after the regimen provided in the examples was taken for 14/30 days;
FIG. 27 is a graph showing the relative abundance changes of the genes involved in alpha-linolenic acid metabolism after administration of the regimen provided in the example for 14 days/30 days;
FIG. 28 is a graph showing the relative abundance changes of the amino acid metabolism-related genes after administration of the regimen provided in the example for 14 days/30 days;
FIG. 29 is the relative abundance change of tryptophan-associated genes after administration of the regimen provided in the examples for 14 days/30 days;
the left panel in fig. 30 is the relative abundance change of genes involved in serotonin biosynthesis after administration of the regimen provided in the examples for 30 days;
the right panel in FIG. 30 shows the relative abundance changes of genes involved in serotonin biosynthesis in a population with relatively weak ability to synthesize serotonin after administration of the regimen provided in the example for 14 days/30 days;
FIG. 31 is the relative abundance changes of genes involved in lysine biosynthesis and metabolism 30 days after administration of the protocol provided in the examples;
FIG. 32 is a graph showing the relative abundance changes of genes involved in acetopropionate biosynthesis 30 days after administration of the protocol provided in the examples;
FIG. 33a is a graph showing the relative abundance changes of endocrine system-associated genes after administration of the regimen provided in the example for 14 days/30 days;
FIG. 33b is the relative abundance change of steroid hormone biosynthesis and metabolism related genes after administration of the regimen provided in the examples for 14/30 days;
FIG. 34a is the relative abundance change of genes involved in lipopolysaccharide biosynthesis after administration of the regimen provided in the examples at 14/30 days;
FIG. 34b is the relative abundance changes of the genes associated with the lipopolysaccharide biosynthesis proteins given for 14 days/30 days according to the protocol provided in the examples;
FIG. 35 is a graph showing the relative abundance change of Pantoea enterobacteria after the regimen provided in the examples was administered for 14 days/30 days;
FIG. 36 is a graph showing the relative abundance changes of genes involved in RIG-I-like receptor signaling 14 days/30 days after administration of the regimen provided in the examples;
FIG. 37 is a plot of the bristol stool scale index change after dosing for 14 days/30 days for the regimen provided in the examples;
FIG. 38 is the change in stool improvement resolution index of Cleveland after 14/30 days following dosing for the regimen provided in the examples;
FIG. 39a is a graph of the change in serum total cholesterol before and after administration 30 days after administration of the regimen provided in the example;
FIG. 39b is a graph showing the change in serum LDL cholesterol before and after administration 30 days after administration of the regimen provided in the examples;
FIG. 39c is a graph showing the change of serum HDL cholesterol before and after administration 30 days after administration of the regimen provided in the examples;
FIG. 40 is a graph showing the change in serum triglycerides before and after administration 30 days after administration of the regimen provided in the examples;
FIG. 41 is a graph showing the change from before to after fasting plasma glucose was administered 30 days after the regimen provided in the examples;
FIG. 42 is a graph showing the effect of improving glucose tolerance test 30 days after administration of the regimen provided in the examples;
FIG. 43 is a graph showing the change in serum uric acid before and after administration 30 days after administration of the regimen provided in the examples;
FIG. 44 is a graph of the change in serum creatinine dose before and after 30 days after dose of the regimen provided in the examples;
FIG. 45 is a graph showing the correlation between the pre-dose concentration of serum creatinine and the post-dose rate of change after 30 days of dosing for the regimen provided in the examples;
FIG. 46 is a graph of the change before and after dosing in volunteers with serum creatinine low 30 days after dosing in the protocol provided in the example;
FIG. 47 is a graph showing the evaluation of the improvement in glomerular filtration rate before and after dosing 30 days after dosing for the regimen provided in the examples;
FIG. 48 is a graph of the improvement in alanine aminotransferase and aspartate aminotransferase after 30 days following dosing for the regimen provided in the examples.
Detailed Description
The compositions in examples 1 to 7 illustrate that: the composition adopts ginseng as the monarch drug. Ginseng is sweet and slightly bitter in taste, warm and mild in nature. It enters spleen, lung and heart meridians. Has effects in invigorating primordial qi, invigorating spleen, benefiting lung, promoting fluid production, and tranquilizing mind. The composition selects ginseng as a representative medicine for tonifying spleen and qi, and spleen governs transportation and transformation, which is acquired root, and spleen qi is healthy to promote qi and blood, so that all things are full of vitality. Spleen qi deficiency failing to transport and transform results in dampness obstruction, qi stagnation and blood stasis. The spleen prefers dryness and dislikes dampness, and if it is damp, it will be abnormal in transportation and transformation. Fu Ling is sweet and bland in flavor and neutral in nature. It enters heart, lung, spleen and kidney meridians, and has the actions of inducing diuresis, excreting dampness, strengthening spleen and calming heart. The composition selects the tuckahoe as a representative medicine for strengthening the spleen and eliminating dampness, and is a ministerial medicine of the composition. Nattokinase, a serine protease produced by Bacillus subtilis natto during fermentation of soybeans, was discovered and named by Aspalathus linearis, ohio, japan. Nattokinase dissolves thrombus by two ways, namely direct and indirect. It can stimulate vascular endothelial cells to produce tissue-type plasminogen activator (t-PA), which activates plasminogen to plasmin, dissolves fibrin and directly dissolves thrombus; at the same time, the prourokinase in the human body is activated into urokinase, and the urokinase and t-PA together activate plasminogen to indirectly dissolve thrombus. Its thrombolytic activity is approximately four times that of plasmin. The composition selects nattokinase as a representative medicine for activating blood circulation and removing blood stasis, and is another ministerial medicine of the prescription. The composition combines multiple species of enteric bacteria low-energy substances. It is basically composed of water-soluble dietary fibers derived from different structures of plant, including pectin, glucomannan, alginic acid and guar gum. Pectin is a water-soluble dietary fiber rich in fruits, and has a straight chain connection of galacturonic acid having carboxyl groups and methyl galacturonate with carboxyl groups esterified by methyl groups. The composition is prepared from pericarpium Citri Tangerinae (total pectin about 33%) rich in various pectins (Chuantelezi, et al, J. Nutrition, 1974), and has effects of regulating qi-flowing, invigorating spleen, eliminating dampness and eliminating phlegm. Glucomannan is a water-soluble dietary fiber rich in konjak plants. The main chain is formed by glucose and diastereoisomers thereof with beta (1-4) bonds, and the branch chain is formed by beta (1-3) bonds or beta (1-6) bonds. Alginic acid is a water-soluble dietary fiber contained in brown algae, and is a linear polymer, and is divided into two types, i.e., β -D-mannuronic acid (M) and C-5 epimer α -L-guluronic acid (G), both of which are monosaccharides with carboxyl groups (1-4). Crude Laminarin (Laminarin), also called Laminarin and brown algae starch, mainly comprises algin, fucoidan, etc., and is composed of beta (1-3) -glucan and some beta (1-6) -glycosidic bonds, and is a neutral glucan. Guar gum is a water-soluble dietary fiber derived from seeds of annual leguminous plants grown in pakistan and india, a polysaccharide consisting of repeating units, with the main chain consisting of mannose and the side chains consisting of galactose. Psyllium husk contains about 90% dietary fiber and is a mixture of insoluble and water soluble dietary fiber. It contains about 18% of polysaccharide heteroxylan, and belongs to water-soluble dietary fiber. The composite water-soluble dietary fiber can provide energy substrates required by different intestinal bacteria. The water-insoluble dietary fiber mainly includes cellulose, hemicellulose, and lignin. Poria cocos is dried sclerotium of Wolf (Schw.) Wolf (fungus of Polyporaceae), has effects of invigorating spleen and eliminating dampness, and is a ministerial drug of the composition, and contains more than 90% of water-insoluble dietary fiber, and has adjuvant effect. Psyllium husk contains about 72% of non-water soluble dietary fiber. The water-insoluble dietary fiber can provide energy substrates for a small part of intestinal bacteria, and more importantly, can increase the water content of the excrement by several times to hundreds of times, thereby increasing the volume of the excrement and facilitating defecation. The above water soluble and water insoluble dietary fibers constitute adjuvants for the composition. Siraitia grosvenorii is used as a guiding drug for introducing drugs into the spleen and large intestine. The mogroside (Mogmside) contained in the composition is 300 times sweet compared with sucrose, has the characteristics of no energy, high sweetness, pure sweetness, high safety and the like, is one of the most excellent natural healthy sweeteners at present, and plays a role in improving the mouthfeel in the composition.
Example 1: composition 1
The above components are crushed, sieved and mixed uniformly to obtain the unit dosage (i.e. the dosage of one pack) of the composition 1 of the invention. The composition can perform bidirectional regulation on the types and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. The composition is administered 1 bag each time, 1 or 2 times daily.
Example 2: composition 2
The formulation of this example can be used as an introduction formulation, or for those who are not suitable for the administration of composition 1 and are accompanied by persistent abdominal distension or pain. The composition can perform bidirectional regulation on the types and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. 1 pack each time (i.e. composition and content shown in the above corresponding table), and is taken 1 or 2 times daily with warm water.
Example 3: composition 3
The formulation of this example is suitable for patients who have a less pronounced or slower improvement in stool on the bristol stool scale (type 4) after taking composition 1 of example 1. The components are crushed, sieved and mixed evenly to obtain the composition 3 unit dosage of the invention. The composition can perform bidirectional regulation on the types and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. 1 bag each time, 1 to 2 times daily, and is taken with warm water.
Example 4: composition 4
In this embodiment, the ginseng total extract may be a commercially available ginseng extract or a ginseng crude extract product.
The components are crushed, sieved and mixed evenly to obtain the composition 4 unit dosage. May be substituted for composition 1. The composition can perform bidirectional regulation on the types and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. It is administered by mixing with warm water 1 bag each time, 1 or 2 times daily.
Example 5: composition 5
The formulation provided in this example can be used as an introduction formulation, or for those who are not suitable for the patient who suffer from persistent abdominal distension or pain due to use of the composition 1 provided in example 1 or the composition 4 provided in example 4. May be substituted for composition 2 provided in example 2. The composition can perform bidirectional regulation on the types and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. 1 bag each time, 1 or 2 times daily, and is taken with warm water.
Example 6: composition 6
Suitable for patients who have not improved the stool significantly or slowly to intermediate type (type 4) of the brix stool test after taking composition 1 provided in example 1 or composition 4 provided in example 4. May be substituted for composition 3 provided in example 3. The components are crushed, sieved and mixed evenly to obtain the unit dosage of the composition 6. The composition can perform bidirectional regulation on the variety and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. 1 bag each time, 1 to 2 times daily, and is taken with warm water.
Example 7: composition 7
Description of the composition: semen Armeniacae amarum (0.25-1 g) and fructus Perillae (0.25-1 g) are added into composition 1-6 as adjuvant drugs. Is suitable for patients with intestinal flora imbalance accompanied with constipation due to intestinal dryness by traditional Chinese medicine diagnosis. According to the diagnosis of traditional Chinese medicine, the utility model is flexible. The content of dietary fiber of semen Armeniacae amarum is more than 10%, and the unsaturated fatty acid is rich in the dietary fiber and has effect in moistening intestine. Perilla seed is rich in unsaturated fatty acids (> 50%) and essential amino acids. Can provide energy substrates for intestinal flora and has the functions of moistening intestines and relaxing bowels for constipation due to intestinal dryness.
The components are crushed, sieved and mixed evenly to obtain the composition 7 unit dosage of the invention. It is applicable to constipation. The composition can perform bidirectional regulation on the types and functions of intestinal flora, and is capable of perfecting and maintaining the diversity of individual intestinal flora. The health-care food plays a role in treating or preventing diseases which can not be well treated at present, such as health maintenance, chronic diseases, metabolic diseases, immune diseases, psychoneurosis and the like. It is administered orally with warm water 1 bag each time, 1 or 2 times daily.
Wherein the spleen invigorating and qi invigorating component includes but is not limited to crude drugs or extracts of Panax ginseng and/or Panax quinquefolium.
Wherein the dampness eliminating component comprises but is not limited to Poria crude drug or extract
Wherein the blood activating component includes, but is not limited to nattokinase, and crude drug or extract of natto.
Wherein the water-soluble dietary fiber comprises one or more of but not limited to glucomannan, pectin, alginic acid, beta-glucan and inulin. Of course, food materials or medicinal materials from which these components can be extracted may be selected.
Wherein the water-insoluble dietary fiber includes but is not limited to one or more of cellulose, hemicellulose and lignin.
The composition is characterized in that the composition comprises 0.01 to 2 grams of crude drugs of ginseng and American ginseng or 0.001 to 0.2 gram of extracts of ginseng and American ginseng, wherein the water-soluble dietary fiber and the water-insoluble dietary fiber are calculated by the total weight percentage of the composition; 0.1 to 5 grams of crude tuckahoe drug or 0.001 to 2 grams of tuckahoe extract; 10-50 g of natto powder or 500-4000 Fu of natto kinase; the water-soluble dietary fiber accounts for 10-70% of the total amount of the formula; the water-insoluble dietary fiber accounts for 10-70% of the total amount of the formula; 0.1 to 3 grams of crude drugs of the momordica grosvenori, or 0.001 to 0.2 grams of extracts of the momordica grosvenori.
The invention is realized by the following technical scheme: four levels prove that the composition can be used for perfecting and maintaining individualized intestinal flora through bidirectional regulation of intestinal flora to prevent or treat various diseases related to intestinal flora functional imbalance from molecular (intestinal flora gene analysis), functional (functional genome analysis), systemic phenotype (Bristol fecal scale), and some representative laboratory detection indexes including blood fat (total cholesterol, triglyceride, low density cholesterol and high density cholesterol), blood sugar (fasting plasma glucose and glucose tolerance test), serum uric acid, renal function indexes (serum creatinine and estimated glomerular rate) and liver function indexes (glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase).
Molecular level resolution was performed by OTU clustering and species annotation. (OTU) analysis Using Vsearchv2.4.4, sequences were clustered into OTUs with 97% similarity by default through de-duplication sequence (- -derep _ fulllength), clustering (- -cluster _ fast, -id 0.97), de-chimera (- -uchime _ ref) (Rognes 2016). Selecting representative sequences of OTUs by using default parameters, performing species annotation on the representative sequences by VSEARCH based on SILVA128 database (Quastet al.2013), generating an OTU list, and obtaining the community composition of samples of phylum, class, order, family, genus and species, and the abundance and classification of all OTUs in each sample. For the quality control of the original sequence data, firstly, whether the data volume of the off-line data tags and the effective data clean tags meets the sequencing requirement is judged, and the data volume of the off-line data generally reaches more than 3 ten thousand reads to meet the sequencing requirement. The average clean tags of the 16s samples in this test are reads of 107670.08, which completely meets the sequencing requirement. The content of OTUs in the sample, which is lower than 0.001% of the total sequence, is limited to the current detection sensitivity and is not used in this experiment.
Functional genome analysis, the number of species of the original 16s sequencing data was first normalized. The predicted function of the genome was then obtained using the most mature tool PICRUSt (PICRUSt Nature Biotechnology,1-10.8 2013) developed earlier, which predicts the function of microbial communities based on the 16S rRNA gene sequence.
Systematic phenotypic analysis, which is performed by using a Bristol Stool Chart (shown in FIG. 1) as a comprehensive index of the diversity of intestinal flora to obtain a Bristol Stool Score index. The judgment method is that the point number of type 4 (normal feces) is 1, the point numbers of type 3 and 5 are 2, the point numbers of type 2 and 6 are 4, and the point numbers of type 1 and 7 are 6. The larger the number of points, the more abnormal the stool. The bristol stool scale is the best test index to reflect the normality of intestinal flora microecology at the phenotypic level of the body (Falony et al science 2016). The purpose of the present invention is to demonstrate that the composition promotes the transformation of the bristol fecal scale into an intermediate phenotype (type 4) by a bidirectional regulatory effect, recombining the intestinal flora structure. That is, constipation can be relieved, and diarrhea can improve diarrhea, rather than simply improving constipation or improving diarrhea.
The Modified Cleveland Stool Score (Modified Cleveland Stool Score) is also used as an auxiliary index for defecation in the present invention. The method can better comprehensively analyze the constipation improvement effect by counting on a Bristol excrement scale and adding various indexes listed in the following table.
A summary of the administration method, administration time, test methods, and statistical treatment is provided below:
* Description of the dosing procedure and time: 1) The administration of the composition 1 or 4 was started (in this example, the following test data were taken with the composition 1 as the starting formulation twice a day, and taken with 250 to 300 ml of warm water). After the medicine is taken, abdominal distension and even abdominal pain appear in some people, and generally, the medicine can be improved or disappeared within two or three days, and the medicine can be taken continuously. 2) If the abdominal distention or even the abdominal pain response lasts for about one week, composition 2 or 5 is used instead (in this example, the follow-up data is based on composition 2 as the adjusted formula). After a week of adaptation, if the stool status (bristol stool scale) responded well, the composition 2 or 5 can be used as a maintenance formula. If the stool condition (bristol stool scale) does not respond significantly, once the bloating abdominal pain response improves or disappears, administration of composition 1 or 4 resumes. 3) If the stool status (bristol stool scale) did not respond significantly after taking composition 1 or 4 weeks, composition 3 or 6 (in this example, the follow-up test data was taken with composition 3 as the adjusted formula) was used instead, and if the stool status (bristol stool scale) responded well, composition 1 or 4 was returned as the maintenance formula. 4) For those with constipation, composition 7 is administered. After taking the composition for constipation improvement, the composition 1 or 4 is returned to be the maintenance prescription.
In the above table, the administration of the drug for 14 days and 30 days was performed in the same batch. Two tests were performed on their stools to confirm the subacute (14 days) and long-term (30 days) intervention effect of the composition on intestinal flora. Meanwhile, the repeated reproducibility of the drug action is also verified through the comparison of the two detection results.
The composition has good bidirectional regulation effect on Phylum (Phylum), class (Class), order (Order) and Family (Family). By bidirectional modulating, it is meant that the composition selectively enhances the functional genome of the relatively vulnerable intestinal bacterial species, or the vulnerable intestinal bacterial species, prior to administration. It is shown that the lower the relative abundance of the species, or functional genome, prior to administration, the greater the increase in the relative abundance of the species, or functional genome, upon administration. The increase of the relative weak strains or the functional genome relatively weakens the strong strains or the functional genome, and can strengthen and maintain the micro-ecological balance of the intestinal flora. The following description of the present invention is simply referred to as bidirectional adjustment, and will not be repeated.
FIGS. 2a to 2d are graphs showing the correlation between the relative abundance of each bacterium before and after administration at the phylogenetic level. Wherein (the abscissa is the relative abundance before taking medicine, and the ordinate is the change rate of the relative abundance after taking medicine, i.e. the relative abundance after taking medicine/the relative abundance before taking medicine, for example, "1" indicates no change in the relative abundance after taking medicine, more than 1 indicates an increase in the relative abundance after taking medicine, and less than 1 indicates a decrease in the relative abundance after taking medicine, and the black dots represent the average value of each phylum, class, order and family of bacteria). The left graph is the correlation graph 14 days after the administration of the drug. The right figure is a related graph after 30 days of administration.
As shown in FIG. 2a, the more the Phylum (Phylum) is, the more the Phylum is the weaker, the higher the degree of increase after administration. After 14 days of administration, a clear negative correlation (left panel of fig. 2 a) was shown, with significant statistical significance, and the statistically significant difference was further increased after 30 days of administration (right panel of fig. 2 a). While in Class (Class) (FIG. 2 b), order (Order) (FIG. 2 c), family (Family) level (FIG. 2 d), 14 days of administration (corresponding to the left panel in the figure) or 30 days of administration (corresponding to the right panel in the figure), there is a very obvious negative correlation, which has significant statistical significance. The composition has good bidirectional regulation effect at the level of the phylogenetic section, can inhibit the relative abundance of dominant bacteria and improve the relative abundance of weak bacteria, thereby improving the functional balance and diversity of intestinal flora.
At the phylum level, the compositions have an inhibitory effect on the relative abundance of the phylum Firmicutes (Bac _ Firmicutes). As shown in fig. 3 (ordinate is relative abundance. Horizontal line in boxplot indicates median, X indicates mean, straight line at both ends indicates 75% range fig. 4, fig. 5, fig. 8, fig. 9a, fig. 9b, fig. 9c, fig. 12, fig. 13b, fig. 13c, fig. 13d, fig. 16, fig. 17, fig. 18, fig. 20a, fig. 20b, fig. 21b, fig. 24, fig. 26b, fig. 27, fig. 29, fig. 31, fig. 33b, fig. 34a, fig. 34b, fig. 35, fig. 36 in which the meaning of coordinate or graph is the same as fig. 3). After 14 days of administration, the Relative Abundance of firmicutes (Relative _ aboundance) decreased by 14.5%, which was statistically significant. After 30 days of administration, the relative abundance continuously decreased by more than 15%, with a statistically significant difference greater than 14 days of administration. Showing the effectiveness of the composition, and long-term intervention effects. Obese patients have elevated firmicutes and the most effective Bariatric surgery (Bariatric surgery) reduces firmicutes abundance (muscogenuri et al 2019; ejtahed et al 2018), suggesting that the composition may not require invasive surgery to ameliorate the excess weight of patients and high frequency associated metabolic syndrome, type II diabetes (or type II diabetes), fatty liver, etc. by reducing the relative abundance of firmicutes. Current research suggests that firmicutes may ferment dietary fiber that humans cannot digest, providing additional energy for humans. In the era of hunger, 39313, this was one of the important contributions of the intestinal flora to help humans to spend famine, but in the times of overeating, this effect has brought about the negative effect of overnutrition.
At the phylum level, the composition significantly increased the abundance of Bacteroidetes, bac _ bacteroidides, of the second dominant phylum. As shown in fig. 4, the relative abundance of bacteroidetes phyla increased by 13.8% after 14 days of administration. The relative abundance increased to 15% after 30 days of administration, which was statistically significant. Demonstrating the effectiveness of the composition, and long-term intervention effects. Bacteroidetes, all with reduced relative abundance in obese patients. The composition is expected to improve the excess weight of patients and often accompanied metabolic syndrome, or type II diabetes, fatty liver, etc. by increasing the relative abundance of Bacteroides (Muscogiuri et al 2019). In addition, the bacteroidetes of inflammatory bowel diseases and patients with Crohn's disease are remarkably reduced, and the bacteroides is one of the causes of the intestinal flora microecological imbalance (Presi at al.2019). The composition can improve the abundance of Bacteroides, and can be used in medicine for treating and preventing chronic inflammatory intestinal inflammation caused by immune dysfunction.
At the phylum level, the composition significantly increased the abundance of Proteobacteria of the third phylum (Bac _ Proteobacteria). As shown in fig. 5, the relative abundance of proteobacteria increased by 23.9% 14 days after administration. After 30 days of administration, the relative abundance increased by over 41%, which was statistically significant. The effectiveness of the composition is proved, and the long-term intervention effect is achieved.
The composition can increase the abundance of other phyla of amblyopia. As shown in fig. 6 (the abscissa indicates relative abundance), the relative abundance of the phylum of amblyopia above the detection limit was mostly increased 14 days after administration, and the examples include: bac _ Actinobacter (Actinomycetes door) 214.15%, bac _ Fusobacteria (Fusobacterium door) 276.83%, bac _ Verrucomicrobia (wartmicola door) 264.62%, bac _ Synergites (intercrophytes door) 169.6%, bac _ EpsilonBacaeota 154.25%, bac _ Patescibacteria135.36%, bac _ Lentisphaera (Myxomycota) 140.67%. Among the above phyla of disadvantaged bacteria, the relative abundance of the phylum actinomycetemcomia and the phylum clostridia may help to improve immune function or increase the therapeutic effect of anticancer drugs (Helmink et al. Nature Medicine 2019). The composition can enhance immunity or increase host susceptibility to anticancer drugs by enhancing the phylum of these weaknesses.
As shown in fig. 7 (relative abundance on abscissa), the same trend was maintained 30 days after administration: bac _ Actinobacteria (Actinomycetes door) 152,14%, bac _ Fusobacteria (Fusobacterium door) 271.65%, bac _ Verrucomicrobia (wartwort door) 251.06%, bac _ Tenericutes (Deuteromycota) 131.05%, bac _ Synergystes (intercrophytes door) 138.46%. The above results demonstrate the effectiveness of the composition on the phylum of the amblyopia, and the long-term intervention effect.
By combining the effects, the composition can inhibit the phylum of the vigorous phylum, enhance the relative abundance of the phylum of the weak phylum (or the phylum of the relatively weak dominant phylum), and present good bidirectional regulation effect. The enhanced phylum of the amblyopia indicates that the composition can help the propagation and maintenance of low-abundance strains, thereby helping to strengthen and maintain the diversity of intestinal flora and keeping the microecological health state of the intestinal flora.
As shown in FIG. 8 (ordinate is Bacteroides/firmicutes ratio), the composition increased Bacteroides/firmicutes ratio. After 14 days of administration, the composition increased the median increase in bacteroidetes/firmicutes ratio by 5%. The administration was carried out for 30 days, with the number of the median increasing to more than 10%, which was statistically significant. Demonstrating the effectiveness of the composition, and long-term intervention effects. The rise in bacteroidetes/firmicutes ratio, a possible beneficial effect on the improvement of the metabolic function of the host, in particular on obesity and diabetes, was demonstrated by several studies and clinical observations (Qin j.at., nature 2010 karlsson fh, nature 2013. The composition can be used for improving metabolic diseases by adjusting Bacteroides/firmicutes ratio.
The gut-brain axis is a concept which exists before, and the research on the intestinal flora is advanced, so that new contents are injected into the concept. For example, autism is often accompanied by digestive tract symptoms such as constipation and monophagia, and in recent years, attention has been paid to the association with intestinal flora. Recent surprising findings demonstrate that a decrease in several specific genera, including Bacteroides, parabacteroides, and an increase in lachnospiraceae (Mao Luojun) are responsible for autistic behavior (causctive) (Sharon et al cell 2019). The composition can remarkably reduce the relative abundance of Lachnospiraceae (figure 9 a), and simultaneously improve the relative abundance of Parabacteroides (figure 9 b) and Bacteroides (figure 9 c). Indicating that the composition is expected to cause an improvement in the symptoms of autism. The composition can be used in medicine for treating and preventing autism, and other diseases caused by dysfunction of the intestinal and cerebral axes.
Research shows that compared with the strain composition, the functional composition of the microorganism is smaller among individuals, and the microbial composition can better reflect the microecological health condition of the intestinal flora. The invention further clarifies the effect of the composition from the functional level by analyzing the functional genome of the intestinal flora. Fig. 10 (abscissa is relative abundance before administration, ordinate is rate of change in relative abundance after administration, and filled circles in the graph are average values of the respective metabolic pathways) shows the results of correlation analysis of the change in the fully functional metabolic pathways (two hundred and thirteen kinds in total) after administration (left graph is the result after 14 days of administration, and right graph is the result after 30 days of administration) and the relative abundance before administration, and the dotted line in the graph indicates the linear trend thereof. As shown in the figure, the composition of the present invention showed excellent bilateral regulation function with correlation coefficient around-0.9 and very significant negative correlation (p = 0.000). This result demonstrates that the composition has a two-way modulating effect on the whole metabolic pathway, showing its usefulness at the global level in the health, enhancement and maintenance of the functional balance and diversity of the intestinal flora.
The present inventors further studied the usefulness of the composition from the following 4 points. First, the promotion effect of the composition on the viability of the intestinal flora itself is illustrated from fig. 11 to fig. 18 from the viewpoint of the core function of the intestinal flora, i.e., the maintenance of the survival and proliferation of bacteria by itself; secondly, it is demonstrated from fig. 19 to fig. 20 that the composition can enhance the catabolism of the intestinal flora to foreign harmful substances, and can help or promote the health of the host human body; third, it is demonstrated from FIG. 21 to FIG. 33b that the composition can promote the increase of the intestinal flora to increase the metabolites beneficial to the host; finally, fig. 34a to 38 show that the composition can regulate the metabolic genome of the intestinal flora and promote the immune metabolic function.
Cell transformation (cellular process) of FIG. 11 (abscissa is relative abundance before taking medicine, ordinate is change rate of relative abundance after taking medicine, solid circles in the figure are average value of relative abundance of relevant genome, dotted line indicates exponential trend) summarizes the basic function of intestinal bacteria survival. Including transcription of genes, transduction of cellular signals, mitochondrial function and metabolism, etc. After taking the medicine for 14 days (left picture), certain negative correlation is shown, and after taking the medicine for 30 days (right picture), the correlation is more obvious and has statistical significance. The dotted line in the figure shows its exponential trend. The medicine has strong promotion effect on the weakest gene functional intestinal flora before being taken for 14 days or 30 days. Indicating that the composition has bidirectional regulation effect on cell transformation.
FIG. 12 (ordinate indicates relative abundance) shows that the composition has an effect of promoting transcription of genes of nuclei under the lower concept of cellular transformation (cellular process). After taking the medicine for 14 days (left panel), the relative abundance of nuclear Gene Transcription associated protein Gene Group (Transcription Related protein Gene Group) is promoted, and after taking the medicine for 30 days, the promotion effect reaches a statistically significant meaning, which indicates the effectiveness of the composition, especially for long-term taking.
FIGS. 13a to 13d (the ordinate of FIG. 13a is the relative abundance change rate before and after taking medicine, the abscissa of FIG. 13b to 13d is the relative abundance, and the dotted line shows the linear trend.) show that the composition has the promotion effect on the cell Membrane information transmission function of the cell transformation (cellular process), and has the strong enhancement effect on the intestinal flora (Membrane Transport Gene Group) which is the weakest cell Membrane information transmission function before taking medicine for 14 days or 30 days. The composition has bidirectional regulation effect on cell membrane information transmission function. The related analysis shows that the composition has a bidirectional regulation effect on the cell membrane information transfer function, and is mainly characterized in that the composition has a good enhancement effect on relatively weak Electron transfer carrier (Electron transfer carriers) genomes, inorganic ion transfer (Inorganic ion transfer) genomes and ion channel (stress ion channels) genomes. Both 14 days and 30 days of dosing exhibited a propensity for enhancement, or a statistically significant enhancement. The function can strengthen the cell information transmission of the weak strains or flora and enhance the survival and multiplication capacity of the weak strains or flora.
Cell transformation includes both DNA Repair (Repair) and regeneration (Replication) functions. As shown in fig. 14 (abscissa is relative abundance before taking medicine, ordinate is change rate of relative abundance after taking medicine, solid circles in the figure are average values of related genomes, dotted line represents exponential trend), although statistical correlation analysis shows only weak negative correlation, it can be seen from the figure that relative abundance increases by about 60% for 14 days or 30 days for the weakest functional genome (Non-homologus end-join). Demonstrating the effectiveness of the composition on a poorly functioning genome. Non-homologous end joining is a special DNA double strand break repair mechanism for eukaryotic cells to join two DNA breaks to each other without relying on DNA homology. The complex is shown to promote DNA repair and regeneration in eukaryotes, including enterobacteria, using non-homologous end-joining repair mechanisms.
As shown in figure 15 (the abscissa is the relative abundance before taking medicine, the ordinate is the change rate of the relative abundance after taking medicine, the solid round dots in the figure are the average value of related genomes, and the dotted line shows a linear trend.), the composition also shows a good negative correlation with the life support functional genome of intestinal bacteria (Cell Growth and Death Gene Group) and has a bidirectional regulation effect.
Cell transformation includes apoptosis and protein degradation by the Ubiquitin system (Ubiquitin system). As shown in fig. 16 (ordinate indicates relative abundance), the composition of the present invention can promote the process of Apoptosis (Apoptosis). Apoptosis is the ordered death of autonomous cells controlled by genes to maintain homeostasis. Apoptotic dysfunction presents with many pathologies, typically abnormal proliferation of cells, such as cancer. The composition has effects in promoting apoptosis and maintaining normal metabolism of cells.
The Ubiquitin system (Ubiquitin system) is another cellular protein degradation chain reaction. The ubiquitin system is involved in most short-cycle protein degradation and in various cellular life processes by regulating the metabolism of intracellular proteins. FIG. 17 (ordinate shows relative abundance) shows that the ubiquitin system associated genome is improved 14 days after the composition is taken, which shows that the composition of the invention has a tendency of promoting the function of the ubiquitin system, and the effect is further enhanced 30 days after the composition is taken, and has a statistically significant difference compared with the effect before the composition is taken. Illustrating the long-term intervention of the composition.
Peptidoglycan is an important component of bacterial cell walls, and this composition exhibits some bidirectional regulation of peptidoglycan Biosynthesis (Glycan Biosynthesis). As shown in fig. 18 (ordinate indicates relative abundance), the relative abundance of glycan biosynthesis-associated genomes increased after 14 days and 30 days of administration, and peptidoglycan biosynthesis exhibited a tendency to increase after administration of the composition of the present invention.
Biodegradation of Xenobiotics (Xenobiotics Biodegradation) is an important function of the gut flora. The heterologous substances include drugs, pesticides, plastic or rubber residues, environmental pollutants, food additives, and the like, most of which are substances harmful to human health. As shown in figure 19 (the abscissa is the relative abundance before taking medicine, the ordinate is the change rate of the relative abundance after taking medicine, the solid circles in the figure are the average values of related genomes, and the dotted lines indicate the exponential trend.), the composition can bidirectionally regulate the biodegradation of the heterogeneous substances by the intestinal flora. Statistics show that 14 days or 30 days of medicine taking have significant negative correlation. The thin dotted line shows the promoting effect of the composition on the weak functional genetic flora. The selective promotion effect is significant to human health.
The following table summarizes the promotion of this composition on the biodegradation of functional genomes of some important heterologous substances. These heterologous substances include the insecticide DDT raw material, the primary carcinogen dioxin, the most widely used herbicide atrazine worldwide, and the like.
Note: in the above table, the increase rate calculation method of each biodegradation associated genome is as follows: [ (relative abundance of genome after 14 or 30 days of dosing/relative abundance of genome before dosing) × 100]
Fig. 20a and 20b (ordinate indicates relative abundance) show the effect of the composition on promoting cytochrome p450 (Cyp 450). Cytochrome p450 can reduce or eliminate the biological activity of heterologous substances, and can promote their elimination from the body. Analysis of cytochrome p450 functional genome with Drug biodegradation (fig. 20 a) and heterologous substance biodegradation (fig. 20 b) shows that after the Drug is taken for 14 days, the promotion tendency is provided, and after the Drug is taken for 30 days, the effect is more enhanced, and the statistical significance is remarkable. The promotion of cytochrome p450 may be the main mechanism of the biodegradation promotion of the above-mentioned heterologous substances including drugs, agricultural chemicals, environmental pollutants, food additives, etc.
Fig. 21a (abscissa is relative abundance before administration, ordinate is change rate of relative abundance after administration, dotted line indicates exponential trend) and fig. 21b (ordinate is relative abundance) show bidirectional regulation effect of the composition on biosynthesis of Polyketides (Polyketides) and terpene compounds (Terpenoids). The decrease in correlation coefficient after 30 days of dosing was due to the increase in the coefficient of Variation (> 1100%) resulting from the sharp rise (> 1100%) of Type II Polyketide Products. Polyketides (Polyketides) are a class of secondary metabolites produced by bacteria, fungi, plants and animals, and can be used in clinical applications as antibiotics (e.g., erythromycin), antifungals (e.g., amphotericin), anticancer drugs (e.g., doxorubicin), immunosuppressants (e.g., rapamycin), and antiparasitics, due to their important biological activities. Terpenes (Terpenoids) are a general term for a series of Terpenoids, and the total number of Terpenoids known at present exceeds 22000. Many terpenoids have important physiological activities, and are also important compounds in Chinese herbal medicines, such as tanshinone compounds, triptolide, stevioside, andrographolide, etc. In addition, diterpene lactone components with anticancer activity such as methyl genkwa ester and ethyl ester can be added. These products not only protect the intestinal flora itself, but also provide the host with beneficial bioactive components. Importantly, as shown by the dashed lines in FIG. 21a, the composition selectively enhances the tendency of the disadvantaged gene group, which may facilitate the synthesis of relatively scarce polyketides and terpenes.
FIG. 22 (abscissa is relative abundance before taking medicine, ordinate is relative abundance change rate after taking medicine, filled circles in the figure are mean values of relevant genomes, dotted line represents exponential trend) shows that the composition has bidirectional regulation effect on coenzyme (Cofactor) and Vitamin (Vitamin) and has stronger promotion effect on weak Vitamin and coenzyme gene group. It is expected to promote and maintain the physiological functions of the host human body by regulating the relatively deficient coenzymes and vitamins.
As shown in fig. 23a to 23c (abscissa is relative abundance before taking medicine, ordinate is change of relative abundance after taking medicine, dotted line indicates linear trend), the composition has good bidirectional regulation function on B vitamin synthesis associated functional genomes including vitamin B1 (fig. 23a left panel), B2 (fig. 23a right panel), B6 (fig. 23B left panel), folic acid (B9) (fig. 23B right panel) and B12 (fig. 23 c). The B vitamins need to work synergistically rather than singly. Therefore, the composition has important significance for the overall improvement of relatively weak functional genomes and the maintenance and improvement of the physiological functions of the whole vitamin B group.
Figure 24, the ordinate being the relative abundance of the Lipoic Acid anabolism (Lipoic Acid Metabolism) -associated genome, shows that the composition has a promoting effect on coenzyme Lipoic Acid. After taking the medicine for 14 days, the improvement tendency is shown, and after taking the medicine for 30 days, the remarkable statistical significance is achieved. The lipoic acid has strong antioxidation, and can reduce the risks of fatty liver and hyperlipidemia and the toxicity of heavy metal to other coenzymes.
As shown in FIG. 25 (abscissa is relative abundance before taking medicine, ordinate is relative abundance change after taking medicine, filled circles in the figure are mean values of related genomes, dotted lines indicate exponential trend), the composition has bidirectional regulation effect on Carbohydrate Metabolism associated functional genomes (Carbohydrate Metabolism Gene Group), and shows enhancement effect on functional vulnerable groups.
FIG. 26a (abscissa is relative abundance before dosing and ordinate is rate of change of relative abundance after dosing. Filled circles in the figure are mean values of the relevant genome. Dotted lines indicate exponential trends) shows the bi-directional regulation effect of the composition on Lipid Metabolism (Lipid Metabolism). Statistical analysis shows that 14 days and 30 days after taking the medicine tend to have negative correlation. As the trend is shown by the dotted line, the composition has strong promotion effect on some very weak functional genomes. Lipids comprise important components of cell membranes (phospholipids), important physiological regulatory substances (including fat-soluble vitamins), and important intermediate substances of biological metabolism, etc., and provide an important material basis for life activities. As shown in the box plot (26 b), the regulation of tissue metabolism by the composition may be partly achieved by increasing Bile Secretion (Bile Secretion).
As shown in fig. 27 (the ordinate indicates relative abundance), this composition significantly increased the abundance of the genome for both synthetic and metabolic functions of Linolenic Acid (linear Acid Metabolism). An enhanced trend was shown after 14 days of dosing and a statistically significant difference was achieved 30 days after dosing, indicating the long-term effectiveness of the composition. Linolenic acid belongs to omega-3 series polyene fatty acid, is a main component forming human tissue cells, and can be synthesized, metabolized and converted into DHA and EPA necessary for organisms. It cannot be synthesized in human body, and synthesis of intestinal flora is one of the sources. Once a human body is deficient, the lipid metabolism disorder of the body can be induced, and the immunity is reduced, the amnesia, the fatigue, the hypopsia, the cardiovascular and cerebrovascular diseases and the like are caused. In addition, linolenic acid is also an important cosmetic medicine.
As shown in figure 28 (the abscissa is the relative abundance before taking medicine, and the ordinate is the change rate of the relative abundance after taking medicine, the solid circles in the figure are the average value of related genomes, and the dotted line represents an exponential trend), the technical scheme of the invention has remarkable bidirectional regulation effect on functional genomes related to amino acid anabolism. The administration for 14 days and 30 days has stronger effect on the weak functional genome of amino acid anabolism.
As shown in fig. 29 (the ordinate indicates relative abundance), the composition has a certain promoting effect on the relative abundance of a functional genome associated with Tryptophan anabolism (Tryptophan Metabolism). Tryptophan is a precursor of the neurotransmitter serotonin. Because serotonin itself cannot pass through the blood brain barrier, it must be synthesized using precursors that enter the brain from the peripheral blood. Tryptophan deficiency can lead to a deficiency of serotonin in the brain. Brain serotonin is a key neurotransmitter in the maintenance of internal drive (appetite, sleep, sex) and mood. The reduced serotonin level is the main cause of the mood depression, depression and bipolar disorder, and may have close relationship with chronic fatigue disease, fibromyalgia and the like.
In addition to the precursors shown in FIG. 29, the compositions also have some bidirectional regulatory function on the functional genome associated with serotonin (5-HT) itself. As shown in FIG. 30, the abscissa of the left graph represents the relative abundance of the gene group related to the serotonin biosynthesis function before administration, the ordinate represents the rate of change in the relative abundance after administration, and the dotted line represents a linear trend. The abscissa of the right panel is the relative abundance change of the group before and 30 days after dosing, and the ordinate is the relative abundance. Each line in the right panel shows the change in relative abundance before and after dosing for one subject, pre shows the relative abundance before dosing, and increase after dosing. As can be seen from the right table of FIG. 30, the relative abundance of the drug before administration (relative index. Ltoreq.16) was significantly improved after administration (right table of FIG. 30). Serotonin itself cannot pass through the blood brain barrier, and serotonin synthesized by intestinal flora mainly acts on peripheral organs, particularly the digestive system. Serotonin is known to be involved in controlling gastrointestinal motility, sensitivity and secretion, and can play a role in regulating the functions of the gastrointestinal digestive system.
Lysine (Lysine) is one of the essential amino acids for humans and mammals, which cannot be synthesized by the body itself and must be supplied from the outside. The enterobacteria have genes for synthesizing lysine. As shown in fig. 31 (relative abundance on ordinate), the composition can increase the relative abundance of the lysine anabolic functional genome, taken for 14 or 30 days. Since lysine is easily destroyed and lacking, it is also called the first limiting amino acid. Lysine has important nutritional significance in promoting growth and development of human body, enhancing immunity of organism, resisting virus, promoting fat oxidation, relieving anxiety and mood, etc.
As shown in FIG. 32 (abscissa is relative abundance before taking medicine, ordinate is change rate of relative abundance after 30 days of taking medicine, dotted line shows linear trend), the composition has bidirectional regulation effect on short chain fatty acid synthesis and metabolism functional gene group for 30 days of taking medicine. Short chain fatty acids include primarily acetic, propionic, and butyric acids. The composition has good bidirectional regulation effect on functional gene groups of acetic acid and butyric acid synthesis and metabolism. Has certain bidirectional regulation effect on propionic acid synthesis and metabolism functional gene group. Acetic acid is the most effective agonist of GPR43 receptor, can promote L cells of ileum endocrine cells to secrete glucagon-like peptide-1 (GLP-1), control inflammatory reaction and the like, and has various physiological activities. It is emphasized that the EC50 of acetic acid on GPR43 is 250-500. Mu.M, whereas the mean concentration of acetic acid in the colon lumen is in the range of 10-100mM, and that GPR43 and ligand should always be saturated, calculated as the mean concentration of acetic acid. However, as shown in figure 32, individuals with relative abundances close to 0, plus a gradient of acetic acid concentration due to very thick mucus layers in the colon, continuous mucus flow and motility, may have insufficient acetic acid concentration to activate the GPR43 receptor. This is an important physiological significance of the ability of the composition to enhance relatively poorly functioning genomes. The major functions of butyric acid include providing colonic epithelial thin Cell energy, inhibiting HDACs (histone deacetylases), anti-inflammatory or immunomodulatory functions (Makki K et al, cell Host Microbe.2018; koh Aet al, cell, 2016). The composition is of great significance in solving the problem of insufficient butyric acid in the population with relatively low abundance.
FIG. 33a (abscissa is relative abundance before dosing; ordinate is change in relative abundance after dosing; filled circles in the figure are mean values of the relevant genome; dashed lines indicate exponential trends) shows the bi-directional regulatory effect of the composition on endocrine functional genomes. The effects of the medicine taken for 14 days and 30 days have obvious statistical significance, and particularly the relative abundance of the functional genome for melanin synthesis (Melanogenesis) of extremely weak cells is increased by 1.6 times to 1.7 times. Melanin in the skin can absorb ultraviolet rays. Preventing the penetration of the artificial wetland to deep parts and the damage to tissue cells, and playing a role in protection.
Fig. 33b (relative abundance on ordinate) shows the stimulating effect of the composition on the biosynthesis of Steroid hormones (Steroid hormon). Steroid hormones are roughly divided into five types: glucocorticoids, mineralocorticoids, and the estrogens, progestins, and androgens of the sex hormones. Glucocorticoids and mineralocorticoids, are involved in a wide range of physiological systems such as inflammation control, carbohydrate metabolism, protein catabolism, blood electrolyte levels and immune responses. The low sex hormone can cause the hypoevolutism of primary and secondary sexual symptoms of children and adolescents, the abnormity of female physiological cycle and gestation period, osteoporosis of postmenopausal women, male and female sexual dysfunction, climacteric syndrome and other related diseases.
The intestinal flora plays a decisive role in the maturation and the function maintenance of the immune system of a host human body. The intestinal flora, as a foreign body, needs to be monitored by the immune system, but as a commensal group, the human immune cells cannot attack them excessively. This balance, in fact, serves to train the human immune system to recognize harmful and harmless foreign substances, and professor Justin Sonnenberg of stanford america visually compares the intestinal flora to control the throttle and brake of the host human immune system. The most problematic problem at present is that the brake function is low, the mild people have food and pollen allergy, and the serious people have immune cells capable of attacking self tissues. Lipopolysaccharide (LPS) plays a key role in throttle and brake in the interaction of intestinal flora on the immune system of a host human body. Lipopolysaccharide acts on TLRs (Toll-like receptors) pattern recognition receptors. Through a TLR4 receptor existing in a target cell, the development and the maturation of a human immune system of a host are promoted, and the effect similar to that of a throttle is achieved. Meanwhile, lipopolysaccharide of the intestinal flora plays a key role in regulating the braking function of the immune system. This effect is achieved primarily by activating regulatory T cells to control the activity of the immune system (Belkaid Y et al, cell 2014, tokuhara D et al, allergology int.2019). Once the regulatory function is reduced, there is a close relationship between immune dysfunction, various allergic diseases such as food/drug/foreign body allergy, eczema, and autoimmune diseases such as type I diabetes, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, multiple sclerosis, rheumatoid diseases, asthma, cancer, etc. Fig. 34a and 34b (the ordinate is relative abundance) show that the composition can significantly improve the relative abundance of the functional genome for lipopolysaccharide Biosynthesis (LPS Biosynthesis Gene Group) and the functional genome for lipopolysaccharide protein (LPS Biosynthesis Proteins), which can help to adjust the immune function of the host human body to be kept in a normal range.
Fig. 35 (ordinate is relative abundance) shows the promoting effect of the composition on the extremely weak bacterium Pantoea (Pantoea, genus level). It is known that Pantoea type lipopolysaccharide can activate macrophages in vivo when administered orally or topically to the skin, and has a good effect on various diseases including hyperlipidemia, diabetes, and atropine dermatitis (Nakata K et al, food Sci Nutr.2014). The composition has the effect of promoting Pantoea bacteria, and further shows the regulation effect on immune function and is useful for immune diseases.
The innate immune system is an important line of defense against pathogen invasion by the body. Innate immunity in addition to the TLRs (Toll-like Receptors) pattern recognition Receptors described above, RLRs (RIG-I like Receptors) are also available. RIG-I belongs to RLRs and triggers interferon expression to inhibit viral infection upon detection of intracellular 5 '-triphosphate double-stranded RNA (5' ppp-dsRNA) of viral origin. Figure 36 (ordinate relative abundance) shows the effect of the composition on RLRs. The composition shows a tendency to improve the functional genome related to the activity of the RLRs after being taken for 14 days, and reaches a statistically significant meaning after being taken for 30 days, thereby illustrating the long-term intervention effect basically matched with the RLRs.
The invention utilizes a Bristol Stool Score (Bristol Stool Score) as a comprehensive index of the diversity of intestinal flora, and analyzes the effect of the composition from a system level. The composition is observed in human body to have remarkable bidirectional regulation effect. As shown in fig. 37 (ordinate indicates changes in bristol stool scale index), bristol stool type indicates that the composition can promote stool convergence towards type 4. After taking the medicine for 14 days, the improvement tendency appears, and after taking the medicine for 30 days, the remarkable statistical difference appears. From the phenotypic level, the composition is proved to be capable of strengthening and maintaining the diversity of intestinal flora and have long-term intervention effect. Defecation was considered as a physical symptom, and the composition was also shown to have a bidirectional improving effect on the symptoms of defecation including constipation or diarrhea.
Improved analytical index of Cleveland Stool Score (Cleveland Stool Score) based on Bristol also showed clear improvement. As shown in fig. 38 (ordinate is change in modified kriveland stool analytical index), the administration for 14 days exhibited significant statistical differences, and the significant therapeutic effect continued 30 days after the administration. From the phenotypic level, it was further demonstrated that the composition could be robust and maintain gut flora diversity and have long-term intervention effects.
In order to further prove the improvement effect of the composition on the body functions, representative laboratory detection indexes of some volunteers with hyperglycemia, dyslipidemia or high serum uric acid are detected. These indices include blood lipids (total cholesterol, triglycerides, low density cholesterol, high density cholesterol), blood glucose (fasting plasma glucose, glucose tolerance test), serum uric acid, renal function indices (serum creatinine, estimated glomerular rate), and liver function indices (glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase).
The administration method was the same as that of the volunteer for the pre-narrative intestinal bacteria test. This is briefly described below: 1) The administration of the composition 1 or 4 was started (in this example, the following test data were taken with the composition 1 as the starting formulation twice a day, and taken with 250 to 300 ml of warm water). After the medicine is taken, abdominal distension and even abdominal pain appear in some people, and generally, the medicine can be improved or disappeared within two or three days, and the medicine can be taken continuously. 2) If the abdominal distension or even abdominal pain response lasts for about one week, composition 2 or 5 is used instead (in this example, the follow-up data is based on composition 2 as the adjusted formula). After a week of adaptation, if the stool status (bristol stool scale) responded well, the composition 2 or 5 can be used as a maintenance formula. If the stool condition (bristol stool scale) does not respond significantly, once the bloating abdominal pain response improves or disappears, the administration of either composition 1 or 4 is resumed. 3) If the stool status (bristol stool scale) did not respond significantly after taking composition 1 or 4 weeks, composition 3 or 6 (in this example, the follow-up test data was taken with composition 3 as the adjusted formula) was used instead, and if the stool status (bristol stool scale) responded well, composition 1 or 4 was returned as the maintenance formula. 4) For those with constipation, composition 7 is administered. After taking the composition for constipation improvement, the composition 1 or 4 is returned to the maintenance prescription. The taking time is one month, and except that the glucose tolerance test is respectively detected once after 14 days and 30 days of taking the medicine, other indexes are detected after 30 days of taking the medicine.
Statistical processing, correlation using Pearson (Pearson) correlation coefficients, using paired t-tests to exclude non-correlations. Inter-group controls, paired t-test was used to compare pre-and post-dose changes (significant differences were assigned p < 0.05).
< dyslipidemia-ameliorating Effect >
The test method comprises the following steps:
volunteers were divided into normal and abnormal groups according to the classification criteria of the National Cholesterol Education Program (Third Report of the National Cholesterol Education Program (NCEP), NIH Publication No. 02-5215). Blood tests were performed before taking the drug and 30 days after the drug. After 9 pm the day before the examination, no food was taken except for drinking water. Serum cholesterol was measured routinely in hospital laboratories using the cholesterol oxidase method and triglycerides using the GPO-PAP enzyme method.
The normal and abnormal blood night test indexes are respectively shown in the following table:
blood index | Normal group | Abnormal group |
Total Cholesterol (TC) | <5.172mmol/L | ≥5.172mmol/L |
Low density lipoprotein cholesterol (LDL-C) | <2.586mmol/L | ≥2.586mmol/L |
High density lipoprotein cholesterol (HDL-C) | ≥1.03mmol/L | <1.03mmol/L |
Triglycerides (TG) | <1.69mmol/L | ≥1.69mmol/L |
< Effect on serum Total Cholesterol >
The basic conditions and data changes before and after administration of 16 normal groups and 14 abnormal groups of 30 volunteers are listed as follows
Figure 39a shows the effect of the composition on total cholesterol. The ordinate is the serum total cholesterol concentration. The left panel shows the effect of the composition on the total cholesterol abnormality group. The composition can obviously reduce the concentration of serum total cholesterol, and has statistically significant difference (p = 0.0058). The right panel shows that the composition has no significant effect on the normal group of total cholesterol. Abnormal elevation of serum cholesterol is closely associated with arteriosclerosis, heart disease, stroke and other types of cardiovascular and cerebrovascular disease (Stamler, j.et al.jama,1986, keys a.et al.am.j.epidemiol.1986). Meanwhile, cholesterol is an important raw material for synthesizing important hormones such as adrenocortical hormone and sex hormone, and physiologically active substances such as bile acid and vitamin D required for digesting and absorbing fat, and is also a main component forming a cell membrane and an important physiological substance for maintaining the functions of human organ tissues. The composition is characterized by a specific reduction in abnormally elevated total cholesterol, but does not affect normal physiological levels of cholesterol concentration.
< Effect on Low Density lipoprotein Cholesterol and high Density lipoprotein Cholesterol >
Serum total cholesterol is the sum of cholesterol contained in lipoproteins in blood, and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are the main components thereof. The invention observes the curative effects of 12 volunteers with normal low-density lipoprotein cholesterol, 18 volunteers with abnormal low-density lipoprotein cholesterol and 30 volunteers. The basic condition of the volunteers and the data changes before and after administration are tabulated below:
figure 39b shows the effect of the composition on low density lipoprotein cholesterol. The ordinate is the serum low density lipoprotein cholesterol concentration. The left panel shows the effect of the composition on the abnormal group. The composition can obviously reduce the concentration of serum low-density lipoprotein cholesterol, and has statistically significant difference (p = 0.005). The right panel shows the effect of the composition on the normal group. The composition also has a tendency to decrease the serum low density lipoprotein cholesterol of the normal group (p = 0.064).
The above results indicate that the composition is characterized by a superior low density lipoprotein cholesterol lowering effect. Low density lipoproteins bind cholesterol, carrying it into peripheral tissue cells. Excessive amounts of low density lipoproteins in blood can form residual particles that accumulate in the vessel wall beneath the vascular endothelium. This is the first critical step in the formation of atherosclerotic lesions, which destroys the integrity of the endothelial barrier and activates pro-inflammatory cytokines and chemokines, promoting the generation of Reactive Oxygen Species (ROS) (Weber, c.et al. Nat. Med.2011), ultimately leading to life-threatening diseases such as angina pectoris, heart attack and stroke. Therefore, LDL cholesterol is generally referred to as bad cholesterol. The invention can obviously reduce overhigh low-density lipoprotein cholesterol, and has important significance for preventing the occurrence of cardiovascular and cerebrovascular diseases and the progression of the cardiovascular and cerebrovascular diseases.
FIG. 39c shows the effect of the invention on high density lipoprotein cholesterol. The composition had no effect on volunteers with normal levels of high density lipoprotein cholesterol. However, some patients with low high-density lipoprotein cholesterol have a greater improvement, although not statistically significant.
The currently clinically used hypolipidemic drugs mainly comprise HMG-CoA reductase inhibitors (statins), cation exchange resin group preparations and small intestine cholesterol transport enzyme inhibitors. The treatment medicines not only have the side effects of dissolving striated muscles, damaging liver and kidney functions and the like, but also influence the physiological function of cholesterol when being used excessively. The composition is prepared from food with homology of medicine and food, has low possibility of side effect, can obviously reduce low density lipoprotein cholesterol (bad cholesterol), specifically improve hypercholesterolemia, does not influence the physiological level of cholesterol, and has great clinical significance.
< Effect on triglyceride >
The invention detects triglyceride. The basic conditions and data changes before and after administration of 9 normal groups, 21 abnormal groups and 30 volunteers in total are listed below:
figure 40 shows the effect of the composition on triglycerides. The ordinate is the serum triglyceride concentration. The left panel shows the effect of the composition on the serum triglyceride profile. The composition can significantly reduce abnormally elevated serum triglyceride levels with statistically significant differences (p = 0.0044). The right panel shows that the composition has no significant effect on the normal group of serum triglycerides. Abnormal elevation of triglyceride levels is an independent risk factor for atherosclerosis, cardiovascular and cerebrovascular diseases (Sandesara p.b., endocr.rev.2019). But at the same time physiological levels of triglycerides play a key role in the energy metabolism of the human body. The composition can selectively reduce abnormally elevated triglyceride levels without affecting normal physiological levels, and is effective in preventing or controlling the onset and progression of ischemic heart disease, myocardial infarction, heart failure, cerebral stroke, etc.
< improving Effect on fasting blood glucose >
Test method
According to the American Diabetes Association (ADA), diabetic volunteers (fasting blood glucose >5.56- <7.5 mmol/L) at the critical or early stage of onset were selected as the fasting blood glucose abnormal group, and fasting blood glucose ≦ 5.56mmol/L as the normal group. Blood tests were performed before taking the drug and 30 days after the drug. After 9 pm the day before the examination, no food was taken except for drinking water. Fasting plasma glucose is measured in a hospital laboratory using a glucose oxidase-peroxidase coupling method. The basic conditions and the change in fasting glucose values before and after administration of the drug were tabulated below for 13 normal groups, 19 abnormal groups, and 32 volunteers in total.
FIG. 41 shows the effect of the composition on fasting plasma glucose. The ordinate is the blood glucose concentration. The left panel shows that the composition has statistically significant difference (p = 0.0048) in the blood glucose level reduction of the blood glucose abnormal group. The right panel shows that the composition had no significant effect on the euglycemic group.
The invention further utilizes a glucose tolerance experiment to observe the improvement effect of the insulin resistance of 8 borderline diabetes or diabetic volunteers. The volunteers received blood tests before and 14 days after dosing, 30 days later. After 9 pm the day before the examination, no food was taken except for drinking water. The next morning, a solution containing 75 g of glucose was orally administered for 30 minutes, 1 hour and 2 hours after 0 minute (before taking glucose), respectively, and venous blood was taken to measure blood glucose levels. The effect of the composition on glucose tolerance tests after 14 and 30 days of administration is shown on the left of figure 42. The figure shows that the medicine of the present invention has the function of inhibiting the rise of blood sugar after the oral administration of glucose solution, and the effect is more obvious after the administration for 30 days, which indicates the long-term curative effect of the medicine. On the right of fig. 42 is a statistical analysis taken at two time points of 30 minutes and one hour of the glucose tolerance test. After 30 days of administration, there was a statistically significant difference between the two time points of 30 minutes (p = 0.044) and one hour (p = 0.019), indicating that the composition of the present invention could improve insulin resistance and enhance the sensitivity of body tissue cells to insulin. Before the onset of diabetes, insulin resistance often appears first, so that the sensitivity of tissues and organs to insulin is improved early, and the diabetes can be prevented. After the diabetes mellitus is developed, because only symptomatic treatment is carried out at present, the medicine needs to be taken for life, and serious complications such as cardiovascular and cerebrovascular diseases, chronic renal function damage, nerve ending nerve damage and the like are generated finally. The composition has effect in improving insulin resistance, and can be used for preventing diabetes.
< ameliorating Effect on serum hyperuricemia >
Test method
Volunteers with serum uric acid of 420 μmol/L (male) and 360 μmol/L (female) were used as the serum uric acid abnormal group, and those with serum uric acid lower than the abnormal group were used as the serum uric acid normal group (Liu AD et al, J Atheroser, theromb.2013). The following table shows the basic condition of 28 volunteers in the normal serum uric acid group (15), abnormal serum uric acid group (13) and the change in serum uric acid values before and after administration. The volunteers performed blood tests before and 30 days after taking the drug. After 9 pm the day before the examination, no food was taken except for drinking water. Serum uric acid was measured by enzyme coupling.
Figure 43 shows the effect of the composition on serum uric acid. The ordinate is the serum uric acid concentration. The right panel shows that the composition has obvious blood sugar reduction effect on the serum uric acid abnormal group, and has statistically significant difference (p = 0.001). The left panel shows that the composition has no obvious effect on the normal group of serum uric acid.
Traditionally, the diseases related to the serum uric acid level are mainly related to symptomatic hyperuricemia caused by uric acid crystallization, such as gout, acute and chronic arthritis, uric acid-derived kidney stones, acute or chronic kidney damage and the like. . In recent years, a large number of epidemiological, clinical and experimental studies show that the proportion of asymptomatic and asymptomatic hyperuricemia in the population is higher, and the proportion is related to the pathogenesis of various systemic diseases such as cardiovascular diseases, cerebrovascular diseases, central nervous system, immune and renal systems, erectile dysfunction of sexual dysfunction diseases, frigidity and the like. The harm degree of the soluble high uric acid to the health of human bodies is far greater than that of gout, and the high importance of the medical science community is received. Although hyperuricemia has great potential danger to human bodies, uric acid is an important physiological substance and has important significance to human health. Uric acid is a powerful Reactive Oxygen Species (ROS) antioxidant and peroxynitrite scavenger. Free radicals can be scavenged, metal ions chelated (Frei B, et al, PNAS 1988, glanzounis GK, et al, curr Pharm Des 2005, sautin YY, johnson RJ. Nucleotides Nucleotides Nucl Acids 2008;). More than half of the antioxidant capacity of human plasma is derived from uric acid, which is a stronger function than folic acid (Yeum KJ, et al, 2004). Uric acid at physiological levels can protect the integrity of vascular endothelium and is also an important mediator of the immune response of human type ii, playing a critical role in the protective antibody response of vaccines (Kool M, et al.j Exp Med 2008, kool M, et al.immuneity 2011.
The composition can control hyperuricemia, does not influence the normal physiological level of uric acid, and has important significance for maintaining the physiological function of uric acid and preventing or treating diseases related to hyperuricemia.
< Effect on improving renal function >
Test method
Serum creatinine and glomerular filtration rate are the basic methods for determining liver function. The invention proves the improvement effect of the composition on the kidney function by detecting the serum creatinine level and calculating the glomerular filtration rate. The volunteers performed blood tests before and 30 days after taking the drug. After 9 pm the day before the examination, no food was taken except for drinking water. The morning, veins were drawn and serum creatinine levels were routinely measured using the creatinine enzyme method. The following table shows the baseline profile of 23 volunteers and the changes in serum creatinine levels before and after dosing.
FIG. 44 is a correlation analysis of serum creatinine levels prior to dosing and changes in serum creatinine concentration after dosing. The ordinate is serum creatinine concentration. The composition has obvious effect of reducing serum creatinine, and reaches statistically significant significance (p = 0.0014). Serum creatinine is one of the best indicators of response to glomerular filtration function. The effect of the composition on reducing serum creatinine concentration reflects the protective effect of the composition on kidney function. High uric acid, high blood sugar and dyslipidemia all cause damage to kidney function. The composition has protective effect on renal function, and can be used for treating hyperuricemia, hyperglycemia and dyslipidemias.
FIG. 45 is an analysis of the correlation of serum creatinine change rate after dosing and serum creatinine level before dosing. The ordinate is the rate of change of serum creatinine concentration, the abscissa is the serum creatinine level before administration of the drug, the filled circles in the graph are the measured data of each patient, and the curve shows a linear trend. The composition has a strong correlation between the reduction degree of serum creatinine level and the serum creatinine level before taking medicine (Correl R = -0.59367), and has a remarkable statistical difference (p = 0.000544). Indicating that the composition has a greater ability to promote excretion from the kidney for volunteers with higher creatinine levels prior to administration. The action form is unique and can be related to the bidirectional regulation effect on the intestinal flora.
FIG. 46 is a graph of the effect of the composition on a fraction of volunteers with serum creatinine levels below 60 μmol/L prior to dosing. The composition had an increasing effect on serum creatinine in these volunteers, with a statistically significant difference (p = 0.013). The basic serum creatinine is not only the best renal function detection index, but also reflects the basic metabolism of the muscle. Its level is often seen in weak states such as muscle decline, emaciation, liver function impairment, etc. The effect may result from the strengthening of the composition and the bi-directional regulation of the intestinal flora. This effect profile further shows the regulatory features of the group and the human body physiological functions.
< Effect on calculation of glomerular filtration Rate (eGFR) >
Calculation method
From the serum creatinine measurements, a calculated glomerular filtration rate (eGFR) was obtained using the chinese modified version of the calculation. eGFR <90mi/L is glomerular pre-rate abnormality group. The following table is the basic information of the volunteers and the data changes after taking the drug.
FIG. 47 shows the change in eGFR after administration of the drug. The ordinate is the calculated glomerular filtration rate. The left panel shows the improvement of the glomerular filtration rate abnormality group with statistically significant differences (p = 0.010) in the composition. The right panel shows the effect of the composition on the normal glomerular filtration rate group, with the same statistically significant difference (p = 0.031). eGFR can reflect renal function levels better than serum creatinine, a means to measure renal function levels and determine the stage of renal disease. When the eGFR value is 60-89ml/min, the kidney is slightly dysfunctional. This stage begins treatment, most hopefully improving or controlling further decline in kidney function. However, no good medicine exists at present, and the composition shows good improvement effect on patients in the period. At eGFR values of 90 and higher, although production functions are in the normal range. But are potential risk factors for renal impairment when accompanied by lifestyle-related diseases such as hyperglycemia, hyperlipidemia, hypertension, obesity, and the like. The composition can reduce the risk of renal function impairment in this class of patients.
< improving action on liver function >
Test method
The invention adopts a hepatocyte damage index threshold value (Bedogni G et al.hepatology 2005) obtained by non-alcoholic fatty liver research, takes a volunteer with more than 30U/L glutamic-pyruvic transaminase or glutamic-oxalacetic transaminase as a target, and observes the change before taking the medicine and after 30 days of taking the medicine. After 9 pm the day before the examination, no food was taken except for drinking water. In the morning, venous blood was drawn and the activity of glutamic-pyruvic transaminase or glutamic-oxalacetic transaminase was determined by a rate method. The following table shows the basic condition of 10 volunteers and the change in glutamate pyruvate transaminase or glutamate oxaloacetate transaminase activity before and after administration.
Figure 48 shows the improvement of glutamic-pyruvic transaminase by the composition on the left side and glutamic-oxalacetic transaminase on the right side (liver function unit on the ordinate). The composition showed statistically significant improvement in both (p =0.027, p = 0.039), demonstrating that the composition has a protective effect on hepatocytes at risk of damage. The function of multiple organs is affected by blood sugar rise and blood lipid abnormality, and the liver is an important organ of the whole body metabolism, and the function abnormality often occurs in the case of hyperglycemia or blood lipid abnormality. The protective effect of the composition on liver function may be partly due to its blood sugar and blood lipid lowering effect.
Claims (21)
1. A composition with a function of perfecting the diversity of the individual intestinal flora is characterized by comprising components for tonifying spleen and qi, components for eliminating dampness and activating blood and intestinal flora energy substrates:
the spleen invigorating and qi tonifying component is one or more of Ginseng radix, ginseng radix extract, radix Panacis Quinquefolii, and radix Panacis Quinquefolii extract; the components for eliminating dampness and activating blood comprise components for eliminating dampness and components for activating blood; wherein the dampness eliminating component comprises one or more of Poria and Poria extract; the blood activating component comprises one or more of nattokinase, natto and natto extract; the enteric bacteria energy substrate comprises water-soluble dietary fiber, water-insoluble dietary fiber or any combination of the two; the daily amount mainly comprises the following components:
wherein the amount of natto or natto extract is calculated by the activity of nattokinase contained therein.
2. The composition with robust and personalized intestinal flora diversity function according to claim 1, wherein the water-soluble dietary fiber comprises one or more of konjac flour, glucomannan, crude laminarin, pectin, alginic acid, dextran, guar gum, inulin, and dried orange peel, or one or more of food materials or medicinal materials containing the above components.
3. The composition with robust personalized gut flora diversity function according to claim 1, wherein the water insoluble dietary fiber comprises one or more of cellulose, hemicellulose, lignin.
4. The composition with robust personalized intestinal flora diversity function according to claim 1, further comprising one or more of luo han guo, luo han guo extract, apricot kernel extract, perilla seed extract.
6. The composition with robust and personalized intestinal flora diversity function according to claim 1, further comprising 0.1-3 g of momordica grosvenori or 0.001-0.5 g of momordica grosvenori extract; or simultaneously or independently comprises 0.25-1g of almond and/or 0.25-1g of perillaseed.
7. The composition with the function of perfecting the diversity of the individual intestinal flora according to any one of claims 1 to 6, characterized in that the water-soluble dietary fiber accounts for 20 to 60 percent of the total amount of the formula; the water-insoluble dietary fiber accounts for 20-60% of the total amount of the formula; the total addition of the water-soluble dietary fiber or the water-insoluble dietary fiber is 1 to 10 grams according to the daily amount.
9. use of a composition according to any one of claims 1 to 8 in the manufacture of a medicament having robust individualized gut flora diversity.
10. The use according to claim 9, wherein the medicament is a medicament for the prophylaxis, or treatment, or co-treatment of a condition associated with an imbalance in gut flora.
11. The use of claim 10, wherein the imbalance in gut flora comprises a low diversity in gut flora species and function.
12. The use of claim 10, wherein the gut flora imbalance comprises a relatively strong species of the dominant gut flora and a relatively weak species of the functional genome and a relatively low species of the weak gut flora and a relatively weak functional genome.
13. The use of claim 10, wherein the disorders associated with imbalanced intestinal flora comprise one or more of metabolic dysfunctional disorders associated with imbalanced intestinal flora, immunologic dysfunctional disorders, skin disorders, neuro-psychiatric disorders, digestive disorders, and disorders associated with low sex hormones.
14. The use of claim 13, wherein the metabolic dysfunction disease comprises one or more of borderline diabetes, type II diabetes, obesity, cardiovascular disease, cerebrovascular disease, hyperlipidemia, hypertension, hyperuricemia, and renal dysfunction.
15. The use according to claim 13, wherein the immune dysfunction disease comprises one or more of food/drug/foreign body allergy, eczema, type I diabetes, irritable bowel syndrome, inflammatory bowel disease, crohn's disease, multiple sclerosis, rheumatoid, asthma, cancer.
16. The use according to claim 13, wherein the skin condition comprises one or more of atropine dermatitis associated with an imbalance in intestinal flora, psoriasis, eczema, acne, skin roughness, skin ageing.
17. The use of claim 13, wherein the neuro-psychiatric disorder comprises one or more of depression, bipolar disorder, autism, schizophrenia, insomnia, parkinsonism, alzheimer's disease, fibromyalgia.
18. The use of claim 13, wherein the digestive disorders comprise constipation, diarrhea, fatty liver, and cirrhosis.
19. The use according to claim 13, wherein the disorders associated with sexual hormone deficiency include hypoevolutism of primary and secondary sexual disorders in children and adolescents, disorders and diseases associated with the physiological cycle and pregnancy in women, osteoporosis due to estrogen deficiency in postmenopausal women, sexual dysfunction in both men and women, and climacteric syndrome.
20. The use of claim 9, wherein the medicament is a medicament having the function of enhancing the biodegradation of exogenous toxic substances by the body; the exogenous toxic substance includes one or more of pesticides, herbicides, food additives, plastic residues, rubber residues, environmental pollutants, heavy metals, and other harmful chemicals.
21. The use of claim 20, wherein said exogenous toxic substance comprises one or more of halobenzoic acid, halocyclohexane, halobenzene, caprolactam, 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine, dioxin, aminobenzoate, xylene.
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